DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ANTI-INFECTIVE DRUGS ADVISORY
COMMITTEE (AIDAC) MEETING
Discussion of Issues Related to Clinical
Trial Design and Analysis in Studying Bacteremia
Due to Staphylococcus aureus and
Catheter Related Bacteremia
Thursday, October 14, 2004
8:20 a.m.
Hilton Gaithersburg
The Ballroom
620 Perry Parkway
Gaithersburg, Maryland
PARTICIPANTS
James E. Leggett, Jr., M.D., Chair
Shalini Jain, PA-C, MBA, Executive Secretary
MEMBERS
Alan S. Cross, M.D.
Celia J. Maxwell, M.D.
Jan E. Patterson, M.D.
Joan F. Hilton, Sc.D., MPH
John S. Bradley, M.D.
Donald M. Poretz, M.D.
Samuel D. Maldonado, M.D.,
MPH
(Industry Representative)
John E. Edwards, Jr., M.D.
CONSULTANTS, SPECIAL GOVERNMENT EMPLOYEES (VOTING)
Thomas R. Fleming, Ph.D.
Christopher A. Ohl, M.D.
L. Barth Reller, M.D.
Nathan M. Theilman, M.D., MPH
CONSULTANT, FEDERAL EMPLOYEE (VOTING)
Patrick R. Murray, Ph.D.
FDA
Mark Goldberger, M.D.
Sumathi Nambiar, M.D.
John H. Powers, M.D.
Alfred Sorbello, D.O.
Janice Soreth, M.D.
C O N T E N T S
Call to Order and Opening Remarks:
James E. Leggett, Jr., M.D. 5
Conflict of Interest Statement:
Shalini Jain, PA-C, MBA 8
Opening Comments:
Janice Soreth, M.D. 11
Regulatory History of Bacteremia Indications:
Alfred Sorbello, D.O. 23
Questions from Committee 40
Epidemiology of S. aureus Bacteremia:
Sumathi Nambiar, M.D. 55
Questions from Committee 74
Microbiological Considerations in Diagnosing
S. aureus Bacteremia:
Patrick Murray, Ph.D. 82
Questions from Committee 103
Open Public Hearing--Extra Session 109
Francis P. Tally, M.D.,
Cubist Pharmaceuticals Inc.
Clinical Trials Issues with Studies of S. aureus
Bacteremia:
John H. Powers, M.D. 131
Questions from Committee 173
Open Public Hearing 208
Tim Henkel, M.D., Ph.D.,
Vicuron
Pharmaceuticals 209
Charles Knirsch, M.D., MPH,
Pfizer
Pharmaceuticals 222
C
O N T E N T S (Continued)
David Shlaes M.D., Ph.D., Idenix
Issues in Studying Catheter-Related Bacteremia:
Janice Pohlman, M.D. 247
Questions from Committee 269
Questions to Committee and Discussion 272
Summary 366
P R O C E E D
I N G S
Call to Order and Opening Remarks
DR.
LEGGETT: Good morning. Today we are gathered to discuss issues
related to clinical-trial design and analysis in studying bacteremia due to
Staphylococcus aureus as well as issues related to clinical-trial design or
analysis in studying catheter-related bacteremia.
It
is going to be, I hope, not a terribly eventful day but eventful,
nonetheless. I think that the problem
that we are faced with, as clinicians, I faced on Friday when I was asked to
see two patients, one a recently end-stage renal-disease patient with diabetes
who has had three MRSA hemodialysis catheter infections since July when she
started dialysis requiring the removal of the catheter and, at the same time,
was called to see a patient because they had Gram-positive cocci in clusters
from their one of two blood cultures and it turned out to be coagulate-negative
Staph and who cared.
So
I think that is going to be sort of the crux of a lot of the problems today.
To
get started, why don't we go around the table and have everyone introduce
themselves.
DR.
MAXWELL: I'm Celia Maxwell, the
Assistant Vice President for Health Sciences at Howard University, an adult
infectious diseases specialist.
DR.
BRADLEY: I am John Bradley, Pediatric
Infectious Diseases, from Children's Hospital in San Diego.
DR.
OHL: Chris Ohl, Section on Infectious
Diseases, Wake Forest University School of Medicine.
DR.
HILTON: Joan Hilton. I am on the Biostatistics Faculty at
University of California, San Francisco.
DR.
MURRAY: Pat Murray, Director of Microbiology
at the NIH Clinical Center.
DR.
RELLER: Barth Reller, Division of
Infectious Diseases and International Health and Director of Clinical
Microbiology, Duke University Medical Center.
DR.
LEGGETT: Jim Leggett, Infectious
Diseases, Providence Portland Medical Center and the Oregon Health and Sciences University.
DR.
CROSS: Alan Cross, Center for Vaccine
Development, University of Maryland.
DR.
FLEMING: Thomas Fleming, Department of
Biostatistics, University of Washington.
DR.
MALDONADO: Sam Maldonado, Global and
Regulatory Affairs, Johnson & Johnson.
I am the industry representative to this committee.
DR.
PATTERSON: Jan Patterson, Medicine
Infectious Diseases, University of Texas Health Science Center, San Antonio and
South Texas Veterans Healthcare System.
DR.
THEILMAN: Nathan Theilman, Division of
Infectious Diseases and International Health, Duke University Medical Center.
DR.
PORETZ: Donald Poretz, Infectious
Diseases in Fairfax, Virginia.
DR.
NAMBIAR: Sumathi Nambiar, Division of
Anti-Infective Drug Products, FDA.
DR.
SORBELLO: Fred Sorbello, Medical
Officer, FDA.
DR.
POWERS: John Powers, Lead Medical
Officer for Antimicrobial Drug Development and Resistance Initiatives in ODE IV
at FDA.
DR.
SORETH: Good morning. I am Janice Soreth, the Division Director for
Anti-Infectives. Let me take the
opportunity to introduce in absentia our Office Director, Dr. Mark Goldberger,
who is on his way. But another person
who is actually here and who directs a sister division, that of Special
Pathogens and Immunologic Drugs which also regulates antibiotic
development. That would be Dr. Renata
Albrecht who sits behind me here.
MS.
JAIN: I am Shalini Jain, Executive
Secretary for the Anti-Infective Drugs Advisory Committee.
Conflict of Interest Statement
MS.
JAIN: Before we begin the meeting, I
need to read a conflict-of-interest statement.
The following announcement addresses the issue of conflict of interest
issues associated with this meeting and is made a part of the record to preclude
even the appearance of such.
Based
on the agenda, it has been determined that the topics of today's meeting are
issues of broad applicability and there are no products being approved. Unlike issues before a committee in which a
particular product is discussed, issues of broader applicability involve many
industrial sponsors in academic institutions.
All
Special Government Employees have been screened for their financial interests
as they may apply to the general topics at hand. To determine if any conflict of interest
existed, the agency has reviewed the agenda and all relevant financial
interests as reported by the meeting participants.
The
Food and Drug Administration has granted general-matters waivers to the Special
Government Employees participating in this meeting who require a waiver until
Title 18 United States Code Section 208.
A copy of waiver statements may be obtained by submitted a written
request to the agency's Freedom of Information Office, Room 12A-30 of the
Parklawn Building.
Because
general topics impact so many entities, it is not practical to recite all
potential conflicts of interest as they may apply to each member, consultant
and guest speaker. FDA acknowledges that
there may be potential conflicts of interest but, because of the general nature
of the discussions before the committee, these potential conflicts are
mitigated.
With
respect to FDA's invited industry representative, we would like to disclose
that Dr. Samuel Maldonado is participating in this meeting as a non-voting
industry representative acting on behalf of regulated industry. Dr. Maldonado's role on this committee is to
represent industry interests in general and not any one particular company. Dr. Maldonado is employed by Johnson &
Johnson.
In
the event that the discussions involve any other products or firms not already
on the agenda for which FDA participants has a financial interest, the
participants' involvement and their exclusion will be noted for the record.
With
respect to all other participants, we ask, in the interest of fairness, that
all persons making statements or presentations disclose any current or previous
financial involvement with any firm whose products they may wish to comment
upon.
Thank
you.
DR.
LEGGETT: Janice, would you like to start?
Opening Comments
DR.
SORETH: Good morning, Dr. Leggett and
special thanks for the academic quarter this morning, members of the advisory
committee, FDA and industry colleagues and other members of the audience.
(Slide.)
I
would like to begin today's talks by telling you what we are going to talk
about today followed by actually talking about it, then summarizing what we
already told you as a segue to the discussion.
I promise we will finish before midnight.
This
is the story of blood and guidance going a bit bad, that of bacteremia as an
indication.
(Slide.)
I
am going to take us first through the District of Columbia, Rockville and White
Oak--you will understand what I mean in just a moment--followed by a tour, very
briefly, of Hollywood, the Washington Redskins, the NHL lockout, Monday morning
quarterbacking--that would be the discussion period--and wrapping up with
credits. I promise you I have not yet
lost my mind.
(Slide.)
We
are back in the District of Columbia. It
is pre-1965. I am in second grade. We have been talking about bacteremia,
sepsis, bacteremic sepsis, septicemia, primary bacteremia and secondary
bacteremia for a long, long time, ever since the FDA was solely located in the
District.
As
far as the Org chart goes back then, and this is all oral history, we were the
Bureau of Biological and Physical Sciences, the Division of Pharmacology and we
were a branch, I think, of Antibiotics.
As I said, my knowledge of this era is entirely derivative.
(Slide.)
Let's
fast-forward to Rockville of the '70s and the '80s where the language for
bacteremia and septicemia began to make it into package inserts. We will hear more about this historical
framework and its details through to the 1990s and the present from Dr. Fred
Sorbello this morning.
The
Org chart was changing. We were becoming
the Bureau of Biological and Physical Sciences, Division of Pharmacology to the
Bureau of Drugs and Biologics, Division of Anti-Infective and, finally, the
Center for Drug Evaluation and Research.
I realize only now I forgot to put Crystal City on there because, once
we went from the District, we went to Crystal City which is in Virginia and
then, ultimately, to Rockville and Gaithersburg, which is where we are now.
The
Division was morphing at the same time.
It was growing. Back in the '70s
and '80s, we were the Division of Anti-Infectives. We were one entity that took care of regulation
of antibiotics, anti-infectives, anti-parasitics, topical antiseptics,
dermatologics, ophthalmologics, anti-fungals, T.B. drugs and antivirals. I am sure I left something out. Let me know at the break.
There
was a split, then, that happened in the latter '80s. I think it was about '88 when the development
of HIV therapies took off, as it should.
So we split and became the Division of Antiviral Drugs as well as the
Division of Anti-Infectives. The
Antiviral therapies together with the Antifungals and the TB drugs, then, went
to the Division of Antivirals.
This
is the late '80's, early '90's.
(Slide.)
By
the time we hit mid-'90's, maybe about 1996, we, as two divisions, were large
again. Portfolios were growing. So we decided to morph at that point into a
third division. So the Ur-Division, as I
like to call it, of Anti-Infectives then became Anti-Infectives, Antivirals and
Special Pathogens and Immunologic Drug Products directed by Dr. Renata
Albrecht.
The
portfolio from Anti-Infectives of quinolones split off to Special
Pathogens. I believe chronic fatigue and
AIDS wasting type of drugs and transplant products and antifungals and
antiparasitics also went to Special Pathogens.
So
we are now three divisions under the leadership of Dr. Mark Goldberger. It is pertinent--the background is pertinent
to today because the topics really touch all of us within the office and
particularly Anti-Infectives and Special Pathogens. We need to be careful as we write the music
that we sing from the same sheet of music.
I
think more on the history of what we have struggled with as a word, bacteremia,
septicemia, will be discussed later today not only by Dr. Fred Sorbello but
also, in terms of clinical-trial design considerations by Dr. John Powers, by
Dr. Janice Pohlman as well as Dr. Sumathi Nambiar.
(Slide.)
As
to the future, we are moving in 2005, we are told, to White Oak. Shalini, correct me if I am wrong, but I
think all that AC meetings will take place there.
MS.
JAIN: Actually no. They won't be able to actually accommodate
the size.
DR.
SORETH: Wonderful. Okay.
To be determined later. Shalini
was just saying that we won't necessarily have the AC meetings at White
Oak. It is our combined campus, a dream
that we have maintained at FDA for a long, long time. Some would say a nightmare, but
whatever. It is off New Hampshire
around the Beltway for Washingtonians.
This
is the laboratory building. Our building
is off to that side. I am a little
challenged directionally. I would submit
to you that we sincerely hope to have the guidance in this arena tucked away by
the time we move to White Oak. So, see,
we have a challenge.
(Slide.)
Hollywood,
where we are told nothing is impossible, where every scientist should remove
the word "impossible" from his lexicon. Christopher Reeve. Nothing is impossible.
(Slide.)
Except
maybe when it comes to the breakdown of skin, invasion of the blood stream and
infection of the patient followed by cardiac arrest, heart failure, coma and
death, for Superman was no match for a bloodstream infection.
(Slide.)
I
think our meeting today will highlight that it takes extraordinary individuals
to recognize that investment and effort in the discovery of new antibiotics and
in the treatments for serious infections, like Staphylococcus aureus
bacteremia, are indeed worth it in the long run. And I know that some of these extraordinary
individuals are in this room today.
They
are prescribing physicians. They are
academicians. They are industry
colleagues. They are FDA colleagues. They are support staff all of whom have, at
heart, the same mission.
(Slide.)
So
what do the Skins have to do with this?
Well, you have to ask yourself the question what do Joe Gibbs, who is
the Head Coach of the Washington Redskins, and the FDA have in common? I will preface my comments by saying I am a
die-hard Eagles fan but it is not why I say this.
Just
like Joe Gibbs, we thought we had put all the right pieces together on the team
with the catheter-related blood-stream infection guidance. That is 1999 and Dr. Janice Pohlman will tell
us a lot more about that later today.
And, just like Joe Gibbs, we watched as the monster just wouldn't get
up.
(Slide.)
We
discussed the catheter-related blood-stream infection guidance hereafter known
as CRBSI at a 1999 advisory committee meeting.
Most of you were probably not here then because we had a different
committee there. But I know Dr. Barth
Reller was there. The U.S. stats would
tell us that roughly there are 200,000 or 400,000 episodes per year. We should be able to study it.
Mortality
attributable somewhere between 10, 25 percent; we thought a definable case
definition--we thought. Lo and behold,
sponsors, many of them, now tell us there are numerous reasons why they have
hit the boards. But I would ask, don't
blame it on my heart; blame it on my youth.
(Slide.)
The
NHL lockout is pertinent here because success, beyond being tied to this year's
salary cap, is determined not by knowing where the puck is, rather knowing
where the puck is going to be, which is sometimes, maybe often, unpredictable
which is probably why they don't want a salary cap in the first place. But the increasing incidence of Staph aureus
bacteremia paralleled by a rise in infective endocarditis, I think, foreshadows
where major players need to position themselves to win, to develop effective
therapies whose risk/benefit ratio we think we understand so that, ultimately,
patients and their prescribing physicians can benefit from this.
(Slide.)
The
issues for discussion are many. Dr. John
Powers will cover these in great detail.
I have made some excerpts and highlights from his talk that will come
later today. But I want you to bear them
in mind as you go through today's discussions and talks. Should primary bacteremia due to Staph
aureus, PBSA, be an indication? And what
exactly would a healthy development program look like? What patient populations would be included in
such a program?
And,
just as importantly, would there be populations that should be excluded,
because we are not really sure they have an infection? Do they have a lab finding? Should endocarditis due to Staph aureus be a
separate indication?
(Slide.)
More
issues for discussion. Should we grant a
separate catheter-related blood-stream infection indication in its own
right? Does it have merit? Does it lack merit? Or, do we fold it into a more general
clinical-trial experience and product label under the rubric of primary
bacteremia due to Staph aureus or under the rubric of complicated skin
infections?
If
we go the separate way, what additional information would you suggest be
collected before, or while, treating other serious Staph aureus infections?
(Slide.)
Finally,
what role do preclinical and early clinical studies play in setting the stage
for faster, larger clinical trials? We
are cognizant of the fact that, in many ways, in drug development, as in life,
time and money are our enemies. We sweat
the small stuff and we ask you today to do the same.
How
many positive blood cultures are required prior to entry into a primary
bacteremia due to Staph aureus clinical trial?
(Slide.)
Last,
screening patients for admission into these clinical trials appears to be
complicated. Do you have any thoughts or
advice for us as to a general approach?
(Slide.)
I
would like to thank Shalini Jain, our Exec Sec contact and organizer for
today's meeting who answered numerous phone calls, E-mails and cell-phone calls
way later than anyone should have made them, myself included; our Office
Director, Mark Goldberger; John Powers; Ed Cox: and Leo Chan; and, at the
Division level, my ever supportive reliable deputy, Lilian Gravrilovich and
members of the division, Sumathi Nambiar, Janice Pohlman and Fred Sorbello.
I
will stop there and turn the podium back over to Dr. Leggett.
DR.
LEGGETT: Thank you.
Let's
move on to the Regulatory History of Bacteremia Indications which will be done
by Dr. Sorbello.
Regulatory History of Bacteremia
Indications
DR.
SORBELLO: Good morning. I am Fred Sorbello, Medical Officer at the
Division of Anti-Infective Drug Products at FDA.
(Slide.)
My
presentation today will focus on the regulatory history of bacteremia and some
of the early regulatory history of catheter-related blood-stream infections as
labeled blood-stream infection indications.
(Slide.)
I
wanted to start with an historical time line to help to focus a little bit on
the history of the development of this whole issue from a regulatory
perspective. It really began prior to
1992, 1993. As Dr. Soreth had described,
there were various types of terminology that were being used in the setting of
labeling for blood-stream infections.
In
1992, the FDA developed a document called Points to Consider. This was a very important document because it
was designed to assist investigators on how to formulate drug-development plans
for infective agents. Since that time, there
have been several anti-infective drug advisory committee meeting where the
issue has been discussed, including 1993, 1998 and 1999 and, obviously, at the
meeting today.
(Slide.)
Just
to give you a little bit of a perspective on the terminology that has been used
for blood-stream infections in antimicrobial, I just have a chart to kind of
compare the historical terminology versus what is used currently. Historically, labels would include terms such
as bacteremia or septicemia or bacteremia/septicemia, bacterial septicemia or
septicemia (including bacteremia.)
Today,
what is used currently is terminology that is in accordance with the Points to
Consider document which is basically site-specific indications with bacteremia
included if bacteremic patients were involved and assessed adequately within
the particular trials.
To
give you a little more perspective on the labeling indications prior to 1992,
1993, the terms "bacteremia" and "septicemia" were those
that were used most commonly. These were
defined as infections that were accompanied by certain types of laboratory
criteria.
Bacteremia
related to the evidence of one positive blood culture, septicemia with two
positive blood cultures. It is important
to note that, at that time, there were no specific clinical-trial protocols
that were really relevant to those indications.
The data was derived by pooling data on bacteremic patients from trials
that involved different sites of infection; for example, trials that might have
looked at pneumonia or urinary-tract infections where bacteremic patients may
have been enrolled.
Also
the clinical context was bit varied in that patients with either transient
bacteremias or, as I mentioned, bacteremias where there may be an identifiable
focus or even bacteremias of unknown origin could have been included amongst
this pooled data.
(Slide.)
1992,
Points to Consider, a very critical document that was developed. Again, it did contain relevant information on
the agency's perspective on specific indications for anti-infective drugs. It really was an attempt to recognize that
different types of infections had different pathophysiology.
The
way labeled indications were indicated was they were referred to as the
treatment of an infection at a specific body site due to a specified
susceptible microorganism.
Drug-development guidelines were provided with the document so that
accurate information could be complied on both the efficacy and safety of the
drug and that information could later be described in product labeling.
(Slide.)
The
1993 Anti-Infective Drug Advisory Committee focused a bit on this issue of
bacteremia in the setting of two issues.
Number one, the consensus document developed by the American College of
Chest Physicians and the Society of Critical Care Medicine where definitions
were published regarding terms such as sepsis and multi-organ failure. In addition, a pharmaceutical sponsor had
proposed a new indication termed bacteremic sepsis in an attempt to try to both
add some specificity and clarify some of the previous terminology in order to
do a particular drug-development study.
The definition of bacteremic sepsis included some of the material from
the consensus document.
(Slide.)
Just
to review briefly the consensus-document definitions, infection was described
as a microbial phenomenon characterized by an inflammatory response to the
presence of microorganisms or the invasion or normally sterile host tissue by
those organisms.
Bacteremia
was defined as a laboratory finding associated with the presence of viable
bacteremia in the blood. The systemic
inflammatory response was a response that can occur with a multitude of
clinical entities and it was basically manifested by two or more of the
criteria that were listed which was temperature greater than 30 degrees C or
less than 36 degrees C, an elevated heart rate of greater than 90 beats per
minute, respiratory rate greater than 20 beats per minute or a PA-CO2 of
less than 32, an elevated white count of 12,000 or a low white-blood count of
less than 4,000 or 10 percent bands.
Sepsis,
then, was defined as an infected patient who exhibited a systemic inflammatory
response.
(Slide.)
This
is a Venn diagram which is adapted from the paper in Critical Care Medicine
which described the consensus document in the definitions. But it was an attempt to try to show how some
of these concepts merge, again illustrating that there is a large focus of
infected patients and some of those patients will exhibit a systemic
inflammatory response syndrome. Those
that do are considered septic.
Bacteremia
essentially refers to the laboratory finding of bacteremia in a blood
culture. Again, just keep in mind that
there can be other non-infectious causes that can produce a systemic
inflammatory response including burns, ischemia, pancreatitis and others.
(Slide.)
So,
getting back to bacteremic sepsis with the consensus definitions and concepts
in mind, bacteremic sepsis was defined at the time as SIRS, systemic
inflammatory response syndrome, due to an infection that was associated with
positive blood cultures but was without hypotension, hypoperfusion or any
evidence of organ dysfunction.
The
definition implied, but it didn't state, that the patient would have an
identifiable focus of infection. Now,
when this concept was discussed by the 1993 Anti-Infective Drug Advisory
Committee, there were a number of issues that were reviewed. I am just going to mention some of them here
at this point.
One
is bacteremic sepsis really a clinically meaningful entity. Could we, really, on a clinical basis,
identify patients who had that entity.
Number two, there were concerns that the population would be rather
heterogeneous because you might be looking at patients with different types of
underlying diseases, different states of immunosuppression, immunocompetence,
for instance.
Positive
blood cultures; it was certainly felt that they do add confirmation and
specificity in identifying an infecting organism but there was some discussion
about whether positive blood cultures could, in some way, be a marker of
prognosis.
Another
issue was the efficacy of a drug in treating a blood-stream infection and
whether it would be possible to extrapolate the efficacy in clearing a
blood-stream infection to being comparable effective in treating an infection
that is, for example, deep within a certain body tissue or site that might be
the source for that bacteremia.
(Slide.)
So,
amongst the discussion at the time in 1993, it was felt that the terms
bacteremia and septicemia as had been used lacked specificity of
definition. Again, there were concerns
about the patient populations that would be studied. There were concerns about the whole concept
of pooling data from various sites of origin, effective origin for bacteremias
and, lastly, whether or not it would be possible on a clinical basis to
actually identify a person who had sepsis infection with a systemic
inflammatory response who would have a positive blood culture versus those who
would have clinical findings without a positive blood culture, was it really
clinically meaningful and could it be identified on the clinical basis.
(Slide.)
The
recommendations from the Anti-Infective Drug Advisory Committee at the time in
'93 was, again, to focus labeling related to the site of infection,
site-specific labeling as had been described through the Points to Consider
Document and then including bacteremia within that context if it was applicable
rather than using terms such as bacteremia or bacteremic sepsis.
(Slide.)
Now
over the following five years, there were no new drugs that had been approved
with the indication of bacteremia. But
bacteremia and this whole concept of blood-stream-infection indications
resurfaced again back in 1998 at the Anti-Infective Drug Advisory Committee.
In
particular, the main topic referred to catheter-related blood-stream
infections. The issues that brought the
issue up for discussion included the observed rising incidence of bacteremia
due to resistant Gram-positive bacteria in particular, the increased incidence
that was noted of intravenous catheter-related bacteremia and well as
bacteremia without an identifiable focus and the whole concept of how to really
utilize data from bacteremic patients in order to analyze and supplement
clinical-trials data since there were really no clinical trials directly
developed with protocols to look at bacteremia specifically.
(Slide.)
Regarding
the issue of bacteremia as an indication, the committee reaffirmed, again,
using the concept of site-specific labeling for secondary bacteremias but also
had some discussion about the concept of a primary bacteremia as a potential
new indication and a fair amount of discussion focusing, again, on
catheter-related blood-stream infections, catheter-related blood-stream
bacteremias as a focus for future studies and potentially an area for future
drug development.
(Slide.)
To
give some follow up regarding the committee's thoughts on catheter-related
blood-stream infections, the issues, again, of the increased incidence of those
types of infections that were noted, the problems of growing antimicrobial
resistance and also the limited antimicrobial armamentarium that would be
available for treatment, but also the lack of the controlled clinical trials
for drug development for agents to treat path-related blood-stream infections.
There
were a number of topics that were discussed including issues of what types of
criteria should there be for catheter removal, what types of both clinical and
microbiologic criteria should be considered, the number and the source of blood
cultures for this potential indication as well as what types of laboratory
studies might be considered to verify concordance of blood culture and catheter
culture isolates such as DNA subtyping was discussed for Staphylococcus
epidermidis.
(Slide.)
So,
following the Anti-Infective Drug Advisory Committee meeting in '98, a working
group was formulated at FDA, the CRBSI Working Group, and a draft guidance was
developed regarding drug development for catheter-related blood-stream
infections. This guidance was then
presented the following year at the 1999 Anti-Infective Drug Advisory Committee
meeting.
(Slide.)
There
was extensive discussion about the draft guidance and a number of issues were
mentioned. I just wanted to point out
some of these discussion issues because I think they are very pertinent to
today's discussion and a number of them are, as yet, undefined and not clearly
resolved.
Number
one was the issue of a heterogenous patient population, again the concept that,
looking at catheter-related blood-stream infections you would potentially be
looking at a large population of patients, different types of underlying
diseases, different types of catheters, tunnel/non-tunnel,
short-term/long-term, and a whole variety of potentially causative
microorganisms.
Number
two was the sample size that might be required.
Again, the thought was it may require a number of patients to screen to
actually identify those who were felt to have a catheter-related blood-stream
infection. In particular, there were
concerns, and in studies such as this, it would be important to get catheter
data, if catheters are indwelling in the patient and what is more frequently
done is they are just pulled and discarded
without being cultured, the lack of catheter data may be a limiting
finding.
The
other issue is the concept of doing microbiologic evaluation and test-of-cure;
is it necessary, what situations would it be necessary and would the lack of
test-of-cure microdata, again, limit evaluation of this type of a study.
There
were also concerns about the lack of a standardized disease definition for
catheter-related blood-stream infection and also the lack of demonstrable
treatment effect for certain types of organisms, especially organisms that are
low virulence that are associated with skin sites such as coag-negative Staph,
Bacillus, Corynebacterium, some of those types of bacteria.
(Slide.)
Another
main area was the lack of standardized procedures as to how to manage an
infected catheter. It was recognized
that there was basically a lack of standard criteria to provide proof of a
catheter infection, should the types of cultures be catheter-drawn and
peripherally blood-drawn blood cultures, should it be based on two blood
cultures, should it be based on quantitative catheter tips, hub cultures. A number of different options were discussed
without any apparent consensus.
The
other issue is, in management, what would be the criteria to remove the
catheter since it was recognized that patients can have different types of
catheters that can be in for different periods of time and also you can have
different infecting microorganisms as there was some discussion of organisms
such as Staphylococcus epidermidis that may not always require removal of the
catheter. Again, what types of criteria
should be thought about in trying to address the catheter-removal issue.
(Slide.)
Last,
microbiological issues that were discussed and I alluded to these a little
bit. Number one, the issue of
quantitative blood cultures and the fact that they are rather limited in their
availability. Most hospitals are not
able to do quantitative blood cultures and what would be some other options to
take a look at. One that was mentioned
was the possibility of looking at differential blood-culture
time-to-positivity.
Again,
concordance of catheter and blood-culture isolates, what type of
catheter-related isolates would be felt to be valid and how would it be
possible to document that there would be concordance and, again, certain types
of coagulase-negative Staph would probably be organisms where that would be an
important issue.
As
I alluded to previously the concept of test-of-cure blood cultures; do you need
to do a test-of-cure blood culture in someone who studied in the context of the
clinical trial for a catheter-related blood-stream infection. If the patient is well and stable and doing
fine, is that really a requirement or should it be reserved basically as a
secondary endpoint for patients where the catheter is retained and they are
basically treated through.
(Slide.)
So,
in summary, I have tried to summarize for you the regulatory history of
bacteremia and some of the early developmental history regarding
catheter-related blood-stream infections.
I have tried to hit on some points such as the revisions and the changes
that have occurred in terminology that has been used in labeling, the Points to
Consider document which has the label-indication concept as basically what is
employed currently and some of the multiple issues that have been discussed at
previous Anti-Infective Drug Advisory Committees in attempting to discuss and
grapple with a lot of the issues about how to study bacteremia,
catheter-related infections and what some of the appropriate criteria will be.
This
afternoon, Dr. Janice Pohlman is going to provide some additional historical
and current perspectives on catheter-related blood-stream infections, in much
greater detail provide more recent information to you.
Thank
you for your attention.
DR.
LEGGETT: Thank you, Dr. Sorbello.
Questions from Committee
Does
anyone have any questions? Don?
DR.
PORETZ: I imagine that the majority of
these patients are hospitalized but not all of them. There are certainly plenty of patients who
have cultures obtained on an outpatient basis and are treated on an outpatient
basis. But, if a patient is in the
hospital, when they are discharged, the diagnoses are put on the front of the
chart and coded. Is that information
accurate many times and who has access to that information, and when you are
trying to figure out the total number of these patients, is there a central way
that information is gathered? Can you
explain that me?
DR.
SORBELLO: I don't know that there would
be a central clearing house or anything for that type of information.
DR.
PORETZ: Does anyone know?
DR.
SORBELLO: I don't know.
DR.
POWERS: Are you asking about ICD9 codes
and their use in diagnosis?
DR.
PORETZ: Yes, essentially. Where does that information--does it get
entered somewhere?
DR.
POWERS: In terms of for us to use, the
FDA to use?
DR.
PORETZ: Central reporting group.
DR.
POWERS: No; we have actually
gone--Janice, you may want to add to this, but we have actually had to go and
actually pay to get that data from people like large HMOs and other folks to be
able to actually collate that information.
However, the CDC has done some studies on the accuracy or lack of
accuracy with some of these diagnoses.
The
probably with ICD9 codes is they are used for billing and people often code
them in terms of the highest amount that they can bill for so that the accuracy
sometimes is not 100 percent, certainly not to the level, the specificity, we
would like in terms of enrolling people in a clinical trial.
Janice,
do you want to add something?
DR.
POHLMAN: You know, I did look into this
and was going to speak to this a little bit in the afternoon, but I think
largely the numbers that are in the literature, you know, you get this wide
range--I tried to look for the ICD9 codes or, I guess, we are heading towards
ICD10. It is really hard to--they are
not coded specifically for that. A lot
of the numbers come from nosocomial surveillance systems that actually may miss
patients that are treated in an outpatient arena as some of these patients
don't even get hospitalized when the bacteremia is discovered as well as
patients that--some of the surveillance systems will just pick up--it depends
on how the hospital is doing surveillance on whether or not they are doing
non-critical-care units. It may just be
they are getting critical-care numbers so the estimates are really subject to a
lot of variation.
DR.
LEGGETT: Alan?
DR.
CROSS: At one point, the arguments in
the infectious-disease community were really on, for example, the length of
therapy for Staph aureus bacteremia based on whether or not there was either a
non-removable or removable focus. It
sounds like, going through your discussion, that really was never a viable
discussion.
I
think if one thinks back on that type of discussion, obviously catheter-related
infections would be a subset of removable foci.
On the other hand, the nonremovable focus would encompass Staph aureus
bacteremia of a multitude of primary foci, whether it was from the skin, the
urine or elsewhere.
That
has never entered into any of the discussions, it sounds like.
DR.
SORBELLO: There had been some
discussions about treatment although there was not a great focus on duration of
treatment. I think part of that was
because of the discussion about how do you really manage the catheter? Who do you identify and can you identify some
type of uniform guidelines of who has a catheter removed, what kind of
catheters remain; is it related to the type of organism; do you treat them
differently if you keep the catheter in versus you take the catheter out.
So
it had been discussed but I think it was kind of folded into some of the other
more structural constructs of how to really go about formulating some type of,
if you could, a uniform management guideline for catheters.
DR.
CROSS: But, looking at the other end of
it, though, of the nonremovable foci, it sounds like a discussion of the origin
of the bacteremia seemed to make a difference in terms of the recommendations. I don't know whether there is any data
presented at those meetings to actually support that point of view.
DR.
SORBELLO: Not specific data that I
remember from the transcripts but, again, the previous Anti-Infective Drug
Advisory Committees felt, overall, that going with site-specific indications
and then tying the terminology of bacteremia to an identifiable focus was most
appropriate for labeling.
I
think part of grappling with catheter-related infections was there was really
no standardized uniform accepted definition of what a catheter-related
infection was let alone best management because everybody has somewhat of a
different way to kind of tailor their approach, again depending on the
organism, the type of catheter, the type of patient.
So
I think treatment is an extremely important aspect of all this and I think it
really folds in as a very important aspect of management. But I think some of the other constructs of
actually how to put the clinical trial together and develop a population appeared
to be somewhat more of a priority in the prior discussions.
DR.
LEGGETT: It has also been a moving
target looking at the new drugs we have looked at that are treating five days
for pneumonia, et cetera.
Chris?
DR.
OHL: Could you outline how the
discussions went parallel to all of--in this time line related to endocarditis
and diagnosis of endocarditis for trials?
DR.
SORBELLO: Actually, there was not much
discussed regarding endocarditis at the prior Anti-Infective Drug Advisory
Committee meetings as far as criteria for a clinical trial, criteria for
labeling. There was not really an
in-depth discussion about that.
As
I say, the '93 Anti-Infective Drug Advisory Committee meeting was basically
grappling with the new definitions that were published of how do you define
what sepsis is, how do you fit that in to the clinical setting and how do you
tie that in, then, to the labeled indications that were used at the time which
were bacteremia and septicemia where there was still a lot of confusion and
discussion about whether they are specific enough and appropriate enough for a
label.
But
there was not really an in-depth discussion about endocarditis as an
indication.
DR.
LEGGETT: Jan?
DR.
PATTERSON: I wonder if you could clarify
for me what we mean when we say primary bacteremia because, as a hospital
epidemiologist, in doing nosocomial infection surveillance, when we look for
catheter-related infections, we want to make sure that there is not another
identifiable site so that it is not a secondary infection.
So
we call it a catheter-related infection and sometimes we even use the term
primary bacteremia. With Staph aureus,
as clinicians, we very often find a source, whether it is endocarditis or an
abscess or the catheter. So I am just
wondering if you could clarify for me what we mean by primary bacteremia versus
catheter-related.
DR.
SORBELLO: The context that those terms
were used in the historical setting was the primary bacteremia either referred
to the patient with endocarditis or the catheter-related infection and that
bacteremias, secondary bacteremias, were where you had some other identifiable
focus, whether it was along with the urinary tract or whatever.
But
primary bacteremia in the historical sense here was used either in the setting
of endocarditis or catheter-related.
DR.
LEGGETT: Barth?
DR.
RELLER: I have had the great privilege
of actually, I think, being at every one of the meetings that Dr. Sorbello--and
the comment that I wanted to make was that he has done a masterful and accurate
capture of the essence of that decade.
I
think history is very important if we are to learn from it. And a few additions. Dr. Cross brought up the question of role of
removal. In fact, that has been
discussed because--not that the answers are in, but the discussion, because the
recognition that removal is of varying degrees of facility in importance in the
outcome but must be considered and that was captured here; that is, whether it
is a peripheral catheter, indwelling, tunneled, et cetera, and also the
organism and the interplay between the organism so that a catheter that has
Candida or Bacillus or a coagulase-negative Staph, the actions may be quite
different based on recognized outcome.
Dr.
Ohl's query about endocarditis; one of the hesitancies, the caution, about an
indication for catheter-associated bacteremia or that the organism makes a huge
difference and the recognition that particularly--not exclusively but
particularly--with Staph aureus, the specter of endocarditis which is a segue
to Dr. Patterson's comment of usually finding a source if the source is
endocarditis but also grappling with the reality that I am sure will be more
discussion today when there is Staphylococcal bacteremia, is the source
endocarditis or is endocarditis a consequence, one of the many consequences, of
the bacteremia regardless of what the initiating source was.
So
one gets into a chicken-egg phenomenon and the organism, the source, the
relative role of removal, the kind of intervention, drainage, removal,
extirpation in terms of valve replacement, that these things are incredibly
complicated.
Again,
for starting points, as Dr. Sorbello said, I mean it is a very complicated
history but it is a complicated topic and he has really captured the main
points. Some of these other things that
have come up, it is not that they were ignored during the time but it is one of
the reasons that the end conclusions were reached at the different points
sequentially because, clearly, the patient population and the options have also
evolved, I mean whether the patient is granulocytopenic and the chemotherapy
and the kinds of catheters and the spectrum or organisms and the resistance
mechanism--I mean, it is a very different world in 2004 from 1992.
The
last thing, very briefly, is I was not in second grade in 1965 like Janice
Soreth. On the other hand, I was not on
the committee in 1965. (Laughter.)
DR.
LEGGETT: Tom and then John and then,
unless there is anything really urgent, let's move on.
DR.
FLEMING: Fred, back on your Slide 12, I
had a follow-up question that was related to Jan's question. Basically, on Slide 12 is you are referring
to catheter-related BSI. You have noted
in that second-to-the-last point that we have got catheter-related bacteremia
and bacteremia with unknown source.
It
is my understanding that your guidance document for CRBSI focuses exclusively
on the former while, when we are going to go on this afternoon and talk about
PBSA, will be inclusive to both. Is that
correct?
DR.
SORBELLO: Yes, because there was
discussion, actually, at the '98 Anti-Infective Drug Advisory Committee as to
whether some proportion of the patients who have an unidentifiable focus but
have catheters in place could actually have been catheter-related. So there was a fair amount of discussion
about that and how to really view them and how to consider them within the
total spectrum.
DR.
LEGGETT: John?
DR.
BRADLEY: In stepping back for a moment
and looking at some of the questions that Dr. Soreth had asked at the very
beginning, in trying to get a protocol with inclusion and exclusion criteria
that will work, the whole issue of the patient who has a fever and looks
bacteremic is one that I think is an even more important issue than drilling
down to how many blood cultures because that defines a small sub-segment of
those who look bacteremic.
Rule
out sepsis is a very common admitting diagnosis in pediatrics, certainly, and
probably in the adult world as well so, to me, one of the biggest hurdles is to
try and figure out empiric therapy for bacteremic disease, suspect bacteremic
disease, and then contrast that with how we are going to define the treatment,
the drugs, the duration, for documented infection whether it be with the
catheter in, with the catheter out, with endocarditis, without endocarditis.
So
the approach to empiric therapy, to the septic patient, I think, is a huge
program and, in the April of 2004 hearing, the details of one of the
pharmaceutical companies trying to study this, it is clear that we need to
further define what empiric operational definitions we can use so that we can
enrich for evaluable patients.
The
critical-care community with I.D. and pulmonary and surgical help made the
first attempt to define SIRS and the septic patient. They were unhappy with their
definitions. They are in the process of
redefining them. Three weeks ago in
Boston, a group of us got together to try and redefine what is the septic
patient because they all look septic.
You just don't know which ones are actually infected or not.
As
you had said, Jim, it is a moving target so those definitions from 1992 have
been changed for adults. We are changing
them for kids. We are not the only ones
that want to study the septic patient.
There are biologics, pressers, all sorts of other people who are with us
in trying to get our arms around what is this patient and what is the
underlying process and how can we study it.
DR.
LEGGETT: Celia?
DR.
MAXWELL: Just one brief question on
Slide 16. While I know that a large
sample-size requirement would be an issue, was there any speculation as to what
kind of a sample size you would need to begin to answer the question?
DR.
SORBELLO: An actual numerical sample
size was not something that was directly discussed, but I think the core issue
really regarding sample size is how do you define a catheter-related
blood-stream infection, what criteria do you need to make that identification
and, again, if you are dealing with a clinical study where there may not be
uniformity in capturing catheter data because catheters are pulled and
discarded without being cultured or there are not exit-site cultures done, et
cetera, you are losing a major piece of information, at least microbiologic
information, that is needed to properly do the study.
So
I think the size of the sample really dovetails with how you define it and what
your criteria are to prove it, that it actually is a catheter-related
blood-stream infection. I think that
tends to restrict the number of patients that can be enrolled because there are
some rather strict microbiologic data that needs to be collected to do that.
DR.
LEGGETT: Thank you, Dr. Sorbello.
Janice,
before we go on?
DR.
SORETH: Just a quick comment to follow
up on Celia's point. I think we are
going to hear more about this from the companies who are going to speak in the
Open Public Hearing setting with regard to their experience with trying to do
the trial, the number of patients screened versus the number of patients
evaluable as it is, no pun intended, a sticking point for catheter-related blood-stream-infection
trials.
DR.
LEGGETT: We are now going to hear from
Dr. Nambiar who is going to talk to us about the epidemiology of Staph aureus
bacteremia.
Epidemiology of Staph aureus
Bacteremia
DR.
NAMBIAR: Thank you, Dr. Leggett and good
morning everybody.
(Slide.)
In
the next twenty minutes or so I will briefly discuss some salient epidemiology
characteristics of Staph aureus bacteremia.
The clinical implications of this cumulative epidemiologic evidence as
it relates to clinical-trial design will be discussed by Dr. John Powers in a
subsequent presentation.
(Slide.)
Although
staphylococci were first described about 125 years ago by Sir Alexander Ogston,
it continues to evoke immense interest and respect among members of the medical
community both because of its tendency to cause severe disease and its tendency
to develop resistance to antimicrobials.
(Slide.)
Staph
aureus is an important cause of bacteremia in hospitals both within and outside
the United States. Data from the SCOPE
project from 1995 to 1998 showed that Staph aureus was the second-most common
blood-stream isolate and it caused 16 percent of all hospital-acquired
bacteremias.
Data
from pediatric institutions over a slightly longer time period showed that
Staph aureus caused 9 percent of all hospital-acquired bacteremias. In a seven-year study from a single
institution in Switzerland which was an acute-care facility, it was noted that
14 percent of all bacteremias were caused by Staph aureus.
Limited
data is available on the incidence of community-acquired Staph aureus
bacteremia. In a study from four
metropolitan areas in Connecticut in 1998, it was noted that the incidence of
community-acquired Staph aureus bacteremia was about 17 per 100,000 persons.
(Slide.)
The
increasing incident of Staph aureus bacteremia is paralleled by an increase in
the incident of infective endocarditis due to Staph aureus. About 25 to 40 percent of native value
endocarditis is now caused by Staph aureus.
In a series of 329 patients with infective endocarditis from a
tertiary-care facility, 40 percent of all endocarditis was caused by Staph
aureus and the frequency of infective endocarditis due to Staph aureus
increased from 10 percent in 1993 to 68 percent in 1999.
(Slide.)
Why
is Staph aureus bacteremia different from other causes of bacteremia? It can present with a wide spectrum of
clinical manifestations ranging from uncomplicated bacteremia to severe
fulminant and often fatal disease.
Complications are common and are often difficult to identify or to
predict.
Given
its protein manifestations, it is difficult to standardize the extent of
diagnostic procedures. There is
significant overlap of infective endocarditis and the two are often difficult
to differentiate clinically. Mortality
from this disease remains high.
Additionally, it poses there issues both related to its development of
resistance to common antimicrobials and uncertainty regarding the optimum
length of therapy.
(Slide.)
The
common risk factors identified for Staph aureus bacteremia include the use of
intravascular catheters, hemodialysis, intravenous drug use and the presence of
underlying illnesses such as diabetes mellitus and immunosuppression.
(Slide.)
Staph
aureus bacteremia has been classified several different ways in the
literature. It can be classified as
community- or hospital-acquired. It is
classified as primary or secondary depending on the absence or presence of an
apparent primary focus of infection. It
is classified as complicated versus uncomplicated depending on the presence or
absence of certain clinical characteristics.
(Slide.)
Although
all patients with Staph aureus bacteremia necessarily have a focus of
infection, it is not always apparent.
How often there is an obvious focus of infection depends upon the series
of investigations performed, the presence or absence of an intravascular
catheter, whether the population consisted primarily or intravenous drug uses
versus non-drug uses, whether the disease was acquired in the community or in the
hospital.
On
an average, there is no obvious focus of infection in about 20 percent of
cases.
(Slide.)
This
is a graph I have taken from a recent paper by Jensen describing the importance
of focus identification in patients with Staph aureus bacteremia. The line in red represents how often an
unknown focus was reported. This is data
compiled from 14 published studies. The
line in blue depicts how often intravascular catheter was reported as the focus
of infection.
So,
in the '90s, the two cross and the frequency of an unknown focus being reported
has significantly decreased while that due to intravascular catheters is on the
rise.
(Slide.)
In
1976, Nolan and Beaty reported in a retrospective study of 105 cases with Staph
aureus bacteremia. This is one of the
earlier descriptions of two fairly distinct clinical populations, the first
group consisting of 63 patients, all of whom had an apparent primary focus in
infection. These patients were more
likely to have hospital-acquired disease.
They tended to be older with a mean age of 55 years. They were more likely to have significant
underlying illnesses. Secondary foci
were less likely and only two out of the 26 patients with infective
endocarditis belonged to this group.
In
the second group of patients, none of them had an apparent primary focus of
infection. They were more likely to have
community-acquired disease. They were
younger with a mean age of 37 years.
They were more likely to use intravenous drugs, more likely to have
secondary foci and 24 out of the 26 cases of infective endocarditis belonged to
this group.
(Slide.)
Subsequent
studies have also documented that patients with community-acquired Staph aureus
bacteremia are more likely to have an unknown portal of entry, more likely to
develop metastatic disease and have a poorer prognosis. All of these most likely reflect the fact
that medical attention is sought later probably after the onset of bacteremia
and before the institution of effective therapy.
How
often Staph aureus bacteremia is community-acquired differs between studies
essentially because of differences in definition. Most investigators would classify it to be
community-acquired if a positive culture developed within 48 hours of admission
to the hospital. However, other
investigators have used longer cutoffs of 72 to 96 hours.
Using
a 48-hour cutoff to define community-acquired disease, Jensen, et al., in their
series of 278 cases of Staph aureus bacteremia from Denmark noted that just
under 50 percent had community-acquired disease.
Another
important factor to consider in the definition of community-acquired Staph
aureus bacteremia is if there was any prior contact with the healthcare
system. In the series by Morin, et al.,
from Connecticut that I referred to earlier, 192 patients had
community-acquired disease and 62 percent of them had some prior healthcare
contact.
(Slide.)
Staph
aureus bacteremia is classified as complicated versus uncomplicated by
different investigators using various definitions. Some authors would classify it as complicated
if a focus of infection was not identified or it was non-removable while others
would classify complicated Staph aureus bacteremia if there was evidence of
metastatic disease, deep-seated infections or other complications such as acute
respiratory-distress syndrome, or DIC.
In
a series of 724 cases described from Duke University Medical Center,
complicated Staph aureus bacteremia was defined as the presence of attributable
mortality, evidence of infection extension or metastasis, embolic stroke or
recurrent Staph aureus infection within the 12-week follow-up period.
The
authors noted the following four risk factors to predict the presence of
complicated Staph aureus bacteremia; a positive blood culture at 48 to 98 hours
later; community-acquired disease; skin findings such as petechia or vasculitis
suggesting acute systemic infection; and persistent fever at 72 hours.
(Slide.)
We
have already heard some discussion about Staph aureus bacteremia and catheters
and, needless to say, it is very controversial.
Reports of increasing association of catheters and Staph aureus
bacteremia pertain both to hospital-acquired and community-acquired disease and
the increasing association with community-acquired disease may just be a reflection
of changing medical practices.
As
with everything else I have presented so far, the definitions, really, vary
between studies. By and large, catheter
is usually considered the focus of infection if there is no evidence of an
alternate source and there is evidence of inflammation or infection at the
catheter-insertion site or a catheter-tip culture is positive for Staph aureus.
However,
in the absence of catheter microbiologic data, either because the catheter was
not removed or the catheter was not cultured, it is often a diagnosis of
exclusion.
(Slide.)
Steinberg,
et al. reported on the association between catheters and Staph aureus
bacteremia over two time periods from Atlanta.
In the first time period, from 1980 to 1983, they noted that 25 percent
of all hospital-acquired Staph aureus bacteremia were related to the use of
intravascular devices. There were no
documented catheter-related community-acquired Staph aureus bacteremia during
this time period.
However,
from 1990 to 1993, they noted that 56 percent of all hospital-acquired
Staph aureus bacteremia and 22 percent of community-acquired Staph aureus
bacteremia were associated with intravascular devices.
In
a larger series of patients, again from Duke University Medical Center, it was
noted that about 50 percent of patients with Staph aureus bacteremia had an
intravenous catheter as the focus of infection.
(Slide.)
The
incidence of infective endocarditis in patients with Staph aureus bacteremia
were really depending upon the patient population studied and the extent of
evaluation performed.
Traditionally,
the following three bedside criteria, as proposed by Nolan and Beaty, in 1976
were used to predict to presence of infective endocarditis in patients with
Staph aureus bacteremia, community-acquired disease, the absence of a primary
focus of infection and evidence of metastatic disease. However, subsequent studies have shown that
infective endocarditis can occur in patients with hospital-acquired disease. It can occur in patients who have an obvious
primary focus of infection and can occur in a population of non-drug users.
In
a series of 59 patients with Staph aureus infective endocarditis, Fowler, et
al., reported that 46 percent, in fact, had hospital-acquired
disease. In a series of 76 patients with
Staph aureus bacteremia all of whom were non-I.V.-drug users 59 had an obvious
portal of entry and 13 of these 59 patients had evidence of infective
endocarditis.
(Slide.)
Infective
endocarditis is often missed based on clinical findings alone. In a ten-year study from Denmark, it was
noted that endocarditis was missed clinically in over half of the 152
pathologically confirmed infective endocarditis due to Staph aureus.
In
a prospective series of 103 patients with Staph aureus bacteremia that was
studied, 26 were noted to have infective endocarditis using the Duke
criteria. Clinical evidence was,
however, seen in only seven patients, five of whom had peripheral emboli and
two had new murmurs. Transesophageal
echocardiogram identified vegetations in 22 patients, abscess in two,
perforation and new regurgitation in one each.
(Slide.)
Risk
factors for Staph aureus infective endocarditis include the presence of native
value disease which historically was associated with rheumatic heart
disease. However, structural
abnormalities such as mitral-valve prolapse, degenerative disease such as
aortic-valve sclerosis and congenital heart disease also predispose to
development of infective endocarditis.
Other
risk factors include the presence of a prosthetic valve, history of intravenous
drug use or prior infective endocarditis and community-acquired disease.
(Slide.)
How
often patients with Staph aureus bacteremia will develop metastatic disease
again varies between studies. On
average, about a third of patients will develop one or more metastatic
foci. In a retrospective study of 281
patients with Staph aureus bacteremia from Switzerland, 27 percent developed
metastatic disease. Common sites
included the joints, kidneys, nervous system, skin and intervertebral
disc. Half the patients had more than
one metastatic focus of infection.
In
a more recent prospective study of 68 patients published in 2000 by Ringberg,
et al., and this was very appropriately titled "To Seek is to
Find." They noted that 53 percent
of patients, in fact, had evidence of metastatic foci. Patients underwent a fairly extensive
evaluation including one or more of the following; X-rays, echocardiogram, bone
or leukocyte scintigraphy.
(Slide.)
Risk
factors for metastatic disease include community-acquired bacteremia, primary
Staph aureus bacteremia, presence of prosthetic devices including orthopedic
devices, implantable pacemakers and defibrillators. The study also suggested that persistent
bacteremia would be an important risk factor for developing metastatic disease.
Among
104 patients with Staph aureus bacteremia, 59 percent of patients with a
positive blood culture, more than 24 hours after starting effective therapy,
developed metastatic disease compared to 17 percent without sustained
bacteremia.
(Slide.)
The
two important issues that come up in the discussion of metastatic disease is
development of metastatic disease always represent lack of drug efficacy. If not, from what time point after
institution of effective therapy can we always attribute it to lack of drug
efficacy. And this will come up again in
the discussion by Dr. Powers later this morning.
There
is some evidence in patients with infective endocarditis that suggests that
once you institute effective therapy, the rate of embolic phenomenon seems to
decline. So, in a retrospective study of
207 patients with left-sided infective endocarditis, it was noted that the rate
of embolic events decreased from 13 per 1000 patient days during the first week
of therapy to less than 1.2 per thousand patient days after completion of
the second week of therapy.
However,
in my review of the literature, I found there is only limited data available
about inpatients with Staph aureus bacteremia regarding the time to development
of metastatic disease. In a small series
of patients, of 39 patients with Staph aureus bacteremia, Libman, et al.,
reported that nine developed metastatic complications, one within the first
week and eight after the first week of positive blood culture, two of whom
developed metastatic disease four weeks after institution of therapy.
(Slide.)
This
has already been brought up for discussion this morning; what is the optimum
length of therapy. It really depends on
the extent of disease and the presence of host risk factors. Generally complicated infections such as
infective endocarditis and deep-tissue abscesses need prolonged duration of
therapy somewhere in the range of four to six weeks.
However,
the appropriate length of therapy for patients with uncomplicated disease is
still controversial. Some investigators
propose 14 days of therapy while others propose longer duration based on higher
complication rates seen with shorter therapy.
(Slide.)
Acute
systemic complications such as the acute respiratory distress syndrome,
disseminated intravascular coagulation and septic shock usually occur within
the first 48 hours. Mortality in
patients with Staph aureus bacteremia in the pre-antibiotic era was as high as
82 percent as reported by Skinner and Keefer in 1942.
Currently,
though, the mortality rates are much lower.
They still remain fairly high, between 16 to 35 percent. Risk factors for morality include the
severity of illness at onset of bacteremia, presence of an unknown source of infection,
older age and noneradicable foci.
About
12 to 15 percent of patients with Staph aureus bacteremia will develop
recurrent disease. Risk factors for
recurrence include the presence of persistent bacteremia, a retained
intravascular device and the presence of noneradicable foci.
(Slide.)
So,
in summary, these are some of the important challenges we have identified with
Staph aureus bacteremia most of which have a bearing on the design and conduct
of clinical trials. Clinically, it is
classified several ways; community- versus hospital-acquired, primary versus
secondary, complicated versus uncomplicated.
Due to its overlap with infective
endocarditis, there is often a need for echocardiographic evaluation.
Because
of its propensity to cause metastatic disease, there is often a need for
extensive diagnostic procedures and as metastatic disease always due to drug
effect is still unclear. The association
with intravascular catheters is sometimes based on stringent laboratory
criteria but often is a diagnosis of exclusion.
Treatment
issues posed with Staph aureus bacteremia include the need to initiate empiric
therapy given the nature of the disease, the choice of initial therapy which
often is based upon the resistance patterns in any given institution and the
uncertainty regarding the need for short versus long-course therapy.
Thank
you.
DR.
LEGGETT: Thank you, Dr. Nambiar.
Questions from Committee
DR.
LEGGETT: Does anyone have any
questions? Tom?
DR.
FLEMING: I am trying to understand the
sequelae for what might be, in fact, a PBSA cohort. We have seen that there are several important
clinical consequences that you have referred to that are mortality,
endocarditis, metastatic disease. And
the evidence that you have shown, if I am understanding it, would suggest that
effective antimicrobial therapies delivered sufficiently early in time could
have an important benefit in reducing the metastatic-disease rates.
Is
that also true for the ability to reduce the rate of I.E. and mortality and would
we be able to see those effects, particularly on mortality, by only following a
moderate period of time because, as I understand from this, a lot of the
mortality is, in fact, within 30 days.
DR.
NAMBIAR: Even though there is some
evidence to suggest that once you institute appropriate therapy, the likelihood
or the risk of developing metastatic disease is decreased. I think what is not clear at this point is is
there a difference if metastatic focus manifests for the first time in the
first week of illness, whether it manifests in the second week or in the fourth
week, especially some metastatic foci like bone infections may not be evident
early on.
So
what is not clear to us, and we are seeking help from the committee, is from
what point on do we attribute it completely to lack of drug efficacy. The other important issue that comes up is
this drug that we are going to develop to treat Staph aureus bacteremia, should
it have penetration to every potential site where Staph aureus can develop a
focus of infection.
DR.
FLEMING: Just to follow up on that,
certainly some of these events are events that would have been seeded prior to
the initiation of the antimicrobial therapy.
Some, however, presumably will be prevented which I would think would be
a major benefit of such therapy.
So,
for infective endocarditis, is it reasonable to presume that we would be able,
because of this chicken and egg--presumably some of this is, in fact, caused by
Staph aureus bacteremia--is it plausible to think that, with effective therapy,
we should be able to detect a reduction in the incidence cases post-therapy of
I.E.?
DR.
NAMBIAR: Yes, provided you have done
everything to exclude I.E.
DR.
FLEMING: Certainly, that would mean, and
I follow you on that--that would reduce the diluting if we have done as much as
we could to exclude cases that are already preexistent.
DR.
NAMBIAR: I think, in my understanding,
that would be a fair assumption.
DR.
LEGGETT: Tom, there is the other problem
of effective treatment and losing, nonetheless, because a good proportion of
folks who have endocarditis lose their valve four to six weeks into therapy
when cultures are sterile. So that just
further complicates that.
Jan?
DR.
PATTERSON: It was a nice review. I just wanted to comment that since that
Jensen review, there has been the emerging problem of community MRSA which has
affected the rate of community Staph aureus in general. Indeed, it does appear to be a different
epidemiology in terms of the invasiveness of the infection and the fact that
people may even stay bacteremic on bactericidal therapy for Staph aureus.
So,
probably, it is with the PBL talks that those particular strains have--that
would probably be considered a risk factor, I think, for morbidity and
mortality as well.
DR.
LEGGETT: As well as an incentive for
drug companies to produce new drugs.
Joan?
DR.
HILTON: It seems to me that, in trying
to decide whether a therapy is effective, it would be great if there is time to
evaluate a patient's baseline status, then treat, then evaluate the effective
therapy. I am wondering if there are
patients in whom there is not time to evaluate that baseline status that it is
imperative that you start therapy right away.
If
there might be a different group of patients in whom you actually can take a
number of days or whatever time is needed prior to starting therapy, I think
this leads into clinical-trial design.
DR.
NAMBIAR: I think that would be an issue
because I think, given the nature of the beast, I don't think we have the
luxury of waiting for a few days before you actually initiate therapy. In fact, you are more likely to have a
situation where most patients would have received some empiric therapy, I think
like the example Dr. Leggett said. All
that you would know is that there are Gram-positive cocci in clusters.
If
you all those risk factors, you are going to assume it is Staph aureus and,
more than likely, I, as a clinician, wouldn't hold back treatment. So I think having the luxury of waiting for
some time and then evaluating the patient--and, again, the other issue that
comes up is how much evaluation is good enough.
Do you subject every patient to every test that is known because this
particular organism has a propensity to seed in multiple sites.
So
I think part of it is going to be a clinical judgment issue because I think it
is hard to mandate that every patient be subjected to every radiologic
procedure available to detect a potential occult focus.
DR.
LEGGETT: Certainly expensive. Joan, I think part of the problem is we are
trying to get at a final common pathway, final common denominator, and there
are multiple ways to go there. So we
oftentimes tell our residents to sit tight and don't start antibiotics until
you know what is going on.
But
then there are the other people who are deathly ill that we start right away.
Don?
DR.
PORETZ: Just in answer to your question,
also, there are significant medical-legal questions because I have reviewed
multiple files and, if you suspect a bacteremia and you don't act on it, and a
patient is bacteremic, the medical-legal repercussions are very, very
significant.
DR.
LEGGETT: As long as the outcome is bad.
John?
DR.
BRADLEY: I was going to mention, as Jan
did, that, as we move forward, looking at PVL-positive community-acquired MRSA
is going to be incredibly important because the disease is firmly within
pediatrics right now and at the IDSA meetings a week or two ago, the warning
was put out that children get it first and watch out, adults; you are next.
The
other issue that had to do with waiting to start antibiotics, it is the
standard of care right now in a child who has fever to start antibiotics while
your blood cultures are pending. In
order to go through a human research committee to present to a parent, mother
or father, that we are withholding antibiotics and the potential complications
is death I don't think would go over very well.
DR.
LEGGETT: Chris?
DR.
OHL: Just one other comment to add on
that. I think that we are also
discovering that Staph aureus in its resistance has become somewhat
heterogeneous. More difficult to predict
what and whom might respond to therapy that would thought to be sufficient
based on microbiological MIC data. We
are still learning on this issue and it will be some time before that comes to
fruition.
DR.
LEGGETT: Thank you, Dr. Nambiar. If there are no further questions, we will
move on.
Dr.
Patrick Murray is now going to talk to us about Microbiological Considerations
in Diagnosing Staph aureus Bacteremia.
Dr.
Murray?
Microbiological Considerations
in Diagnosing Staph aureus
Bacteremia
DR.
MURRAY: Thank you.
(Slide.)
John
Powers asked me if I would give an overview of the microbiology of the issues
that we are discussing today. I notice
we are running a few minutes overtime.
Hopefully, I won't exacerbate that problem. I think that I would be able to cover this
material within the allotted 20 minutes or so.
(Slide.)
What
I am going to do is divide my presentation into three components. I will start off with an overview of the
blood-culture systems and I think the theme that I want to get across in that
portion of the presentation is that not all negative cultures are created
equally. We tend to think that a
negative culture means really there are no bacteria there. I think what I can do, when I finish this
presentation, is emphasize where, in fact, we can go wrong and miss the
opportunity to detect organisms in the bloodstream.
I
will then talk a little bit about interpretation of the culture results and
then, finally, the last maybe half of the presentation will be on
identification of staphylococci, both the traditional methods for identifying
the staphylococci as well as the newer genetic approaches to this.
(Slide.)
If
we start off with an overview of blood-culture systems, the first thing that we
have to do is collect an uncontaminated blood sample. Skin antisepsis is pretty well defined, what
should be done. The surface to the skin
should be cleaned with 70 percent alcohol.
It should be allowed to dry, air dry.
Then that is followed by either a 2 percent tincture of iodine, povidone
iodine, or chlorhexadine.
Of
the three disinfectants that I just mentioned, the povidone iodine which is
traditionally the disinfectant that has been used most commonly is probably the
least effective and that is because it needs to be on the skin surface for
about two minutes for it to kill the bacteremia that are there.
2
percent tincture of iodine or chlorhexadine both work much faster and, for that
sense, it is probably more effective at least based on traditional practices.
The
other question that could be raised is what is considered an acceptable rate of
contaminated blood cultures. I would say
that there is no acceptable rate. We
don't want to have contaminated blood cultures.
But, generally, the goal of institutions is to keep the contamination
rate below 3 percent.
In
my experience, what we find is that, although you may have a rate of less than
3 percent, in certain parts of the hospital, you may have much higher
rates. Emergency departments is a good
example of that where the contamination rate can be much higher.
I
think in any sort of a program for reducing contaminated blood cultures, it is
important for the institutions to know where their problems are and address
those specifically.
The
volume of blood is the most important aspect of collecting a successful blood
culture. Most septic patients have less
than 1 organism per milliliter of blood, whether that be bacteremia or fungi,
that theme applies. So the more blood
you collect, the greater the chance of getting a positive blood culture. There have been a number of studies that have
looked at that.
Those
studies, then, form the foundation for the current recommendations that, for an
adult patient between 20 to 30 milliliters of blood should be collected for
each blood culture and that volume of blood is divided into two or three
bottles. For children and for infants, there is proportionately less blood that
would be collected.
The
dilution of blood in the broth is also important. The minimum dilution is a 1 to 5 ratio
between the blood to the broth that is in the culture systems. Now, there are resin media that are available
that allow you to have a more concentrated amount of blood in the broth. I tend to think that that is not a good
practice. I think what we want to do is
maximize the amount of growth medium that is available to support the growth of
the organisms.
The
number and timing of cultures really depends on the type of--I am almost afraid
to use the term bacteremia or septicemia right now, so I will use it in a more
generic sense of bacteremia. The number
and timing is really dependent on the type of infection. If it is a continuous infection, and that
would be an intravascular infection like an infection localized on the heart
valve or on a catheter, then, really, the timing is not critical because the
bacteremia will always be present in the bloodstream.
The
key, then, is to collect enough blood to detect to organisms that are
there. On the other hand, if it is a
localized focus, say, a lung or urinary tract or an abscess, then we would
expect that, for many of those patients, you are going to have intermittent
spillage of organisms into the blood and so the timing becomes critical and the
number of cultures that are collected becomes critical.
The
recommendations are that two to three blood cultures should be collected within
a 24-hour period of time. Additional
blood cultures really are not terribly useful unless you are looking for
specific fastidious organisms.
The
methods that we use to culture bacteria and fungi in the blood have evolved
over a number of years. The manual
methods, which consisted of bottles of nutrient media, really have been
replaced by automated methods today. I
think there are very few laboratories that would have a manual method where
they would inoculate the bottles and then periodically look at the bottles to
see if there is evidence of microbial growth in those bottles.
The
lysis centrifugation system is a technique where you draw blood into a vacuum
tube. It has a lysine reagent in the tube which lyses the blood
cells. You concentrate the organisms by
centrifugation and then you take the pellet and you inoculate solid media with that. The advantage of that system is that you can
do a quantitative blood culture.
The
disadvantage is the lysine solution can lyse some organisms that you are
interested in. Staphylococcus pneumoniae
is a good example of that. In addition,
there is a higher incidence of contamination of those cultures because of the
manipulations.
Most
laboratories today use an automated method for processing blood cultures. There are three major players on the market
today in the United States. Each of them
are detecting growth or organisms by the metastatic activity of those organisms
and that could be the production of carbon dioxide, the consumption of oxygen,
and both of those can be detected by sensors or it could be detected by changes
in pressure within the bottles.
Those
systems are comparable. There are subtle
differences between them, or among them.
I think each laboratory has their preference in what they would like to
use but I would say all of those are superior to the manual methods that
existed before.
(Slide.)
If
we look at the interpretation of the culture results, the first is the time to
detect the positive culture. I could say
that most positive cultures, probably 90 percent of more of the positive
cultures that are detected in the laboratory are detected within the first
48 hours of incubation. That is one
of the advantages of the automated systems.
The manual systems took longer in order to detect a positive culture.
Organisms
like Staph aureus, the Enterobacteriaceae, betahemolytic streptococci, all of
those will grow generally within the first 24 hours of incubation. In contrast, organisms like the
coagulase-negative staphylococci can take more than 24 hours on the average
before you detect their growth.
So
one way of separating those organisms just within the laboratory is that if it
grows quickly and it looks like a staphylococcus there is a greater chance that
that is going to be Staph aureus compared with the other staphylococci.
Cultures
are routinely held in laboratories five to seven days. There are some laboratories that hold bottles
for a shorter period of time. I think
that does compromise their success in isolating some organisms, particularly on
patients that have been started on antibiotics before the blood cultures were
collected from those patients.
Extension
beyond seven days is generally unnecessary unless you are looking for more
fastidious organisms such as those that may cause subacute bacterial
endocarditis.
The
spectrum of organisms recovered blood cultures, this has been touched on
already in one of the earlier presentations; about 10 to 15 percent of
blood-culture bottles--blood cultures--are going to be positive, and they can
be positive in one or both bottles that would be inoculated.
The
most common isolates are the coagulase-negative staphylococci, Staphylococcus
aureus, Escherichia coli, the
Enterococci, Klebsiella and Streptococcus
pneumoniae and probably in that order, although that does vary from
hospital to hospital depending on your patient population.
The
key point, though, is the most common organism that we will see in the
laboratory will be the coagulase-negative staphylococci. Most isolates of Staph aureus, Streptococcus
pneumoniae, the beta-hemolytic streptococci, Enterococci, Enterobacteriaceae,
Pseudomonas, the Gram-negative anaerobes and yeast are going to be
significant. So, if we see those in the
blood culture, generally that is a significant finding.
In
contrast, most isolates of the coagulase-negative staphylococci,
Corynebacterium, Propionibacterium and Bacillus are clinically
insignificant. Each of those are
organisms that can colonize the skin surface and contaminate blood cultures.
So
the important point that I would make there is that the coagulase-negative
staphylococci are the most common organisms we see and also are commonly
insignificant. In contrast, Staph aureus
is the most common significant organism that we see but it is--again, we have
to be able to differentiate that from the coagulase-negative staphylococci.
The
other point that I would make is that the coagulase-negative staphylococci do
cause significant infections but almost always they are associated with either
a contaminated line or another foreign body that is present in the patient such
as the prosthetic heart valve, prosthetic joint and so forth.
(Slide.)
Identification
of staphylococci has evolved over the years and I think, in the last three or
four years, we are getting more sophisticated and I think, also, offer
opportunities here to help with some of the issues that are under discussion
today.
What
I would like to do, though, is to mention that, for blood cultures, the way we
approach identifying organisms is different from how we do with other types of
cultures. Other cultures traditionally
we are going to have the organisms isolated on a plate. We can pick the colonies, set up the
biochemical test and be able to identify the organisms.
Because,
in blood cultures, there are so few organisms in the patient's blood, we are
forced to inoculate the blood into a large volume of broth and grow the
organisms initially in that manner. So
what we are faced with, then, is a bottle with 50 to 100 milliters of broth and
blood with the organisms present.
Now,
we can take those bottles. We can
subculture them and the next day pick isolated colonies and go ahead and do
identification tests, but that is going to introduce a one-day delay. So, traditionally, what most microbiology
laboratories attempt to do are some rapid tests using procedures where we can
concentrate the organisms from the broth and perform our test that way.
Now,
that subculture plate--traditionally, microbiologists will take a plate. They will subculture the organisms onto the
plate. They put it into an incubator and
they don't look at it until the next day.
In fact, if you go and you take that plate after four to six hours, you
can see growth is present there, growth that you can use to set up your
biochemical test and identify your organisms or set up your antimicrobial
susceptibility test and have the results available the next day.
Another
approach would be to concentrate the organisms that are in the blood. But, again, the first approach was to use
differential centrifugation, a low-speed centrifugation, to remove the
erythrocytes that are present and then a high-speed centrifugation to
concentrate the organism. You would take
that pellet of organisms and use that to inoculate your test.
A
different approach to do that is to use the serum-separator, or clot tube,
which are commercially available and you centrifuge your blood in that
tube. Your blood cells would be
concentrated in the bottom of the tube.
The organisms, either bacteria or fungi, are concentrated on the top of
the plug that is there and, above that, would be the rest of the blood.
You
can remove the organisms with a pipette and go ahead and set up your test from
that. Now, you can also take the broth,
itself, and set up tests without concentrating the organisms. The broth can be used for what I will talk
about in a few minutes, the FISH test, or
fluorescent in situ hybridization test, can also possibly be used with
molecular probes and I will discuss that also in a few minutes.
But
you need a heavier inoculum from a subculture plate or from a concentrated
pellet of organisms to perform the coagulase test and the protein-A test. The coagulase test is the ability of a
staphylococcus to clot plasma, a very simple test. It has been historically used to identify
Staph aureus for many, many, many years.
The
recommended plasma that should be used is EDTA rabbit plasma, commercially
available and readily available. The
coagulase enzyme--there are actually two enzymes that we are interested
in. One is bound to the surface of the
bacteria and it is called, very originally, bound coagulase also referred to as
clumping factor. The other one is freely
excreted by the bacteria.
It
makes a different which coagulase you are looking at. For the bound coagulase, you can use a slide
test or a commercial or latex agglutination test to detect the presence of that
coagulase where the free coagulase is detected by a tube test.
Now,
let me explain what each of those tests are.
The slide test--what that means is you take your organisms from that
pellet or from a plate. You suspend it
in a small drop of water and then you mix with that the plasma. If Staph aureus is present, the organisms
will clump together and it happens within about ten seconds.
Another
version of this test is commercial latex-agglutination test where, on latex particles,
they have immobilized the antibodies to the bound coagulase as well as
antibodies to protein-A which is specific for Staph aureus. If the latex particles clump in the presence
of the organism, then that is considered a definitive positive test for Staph
aureus.
The
slide test is positive in about 85 percent of the isolates of Staph
aureus. That percent actually will fall
if you don't have a heavy enough inoculum to be able to perform the test
properly. The latex test has a very good
sensitivity and specificity. It
approaches 97 to 98 percent sensitive and specific.
There
are some organisms that will give you a false positive slide test. I have listed them here on this slide. There are also some organisms that will give
you a false positive tube test. The tube
test is that you take a tube of about a half a milliliter of plasma. You suspend your organism in that and you
incubate it for four to 24 hours.
Almost
all Staph aureus isolates will be positive within four hours with that
test. Some, though, require extended
incubation and you have to incubate them overnight before you can have a
definitive negative test.
What
all this means for the coagulase test is that, if the slide test is positive,
in general, you consider that definitive for Staph aureus and you report
that. If the slide test or latex test is
negative, then you have to confirm that negative reaction with the tube test
which would take four to 24 hours.
Again, the protein-A is just a variation of the latex agglutination
test.
(Slide.)
Genetic
probes for Staph aureus; GenProbe has developed the probe they market as
AccuProbe that is used to identify Staph aureus. It is a single-stranded DNA probe with a
chemiluminescence label on it that is complementary to the ribosomal RNA in
Staph aureus. The advantage of targeting
ribosomal RNA is there are about 10,000 copies of the RNA that is present so
you have an inherent amplification of the test using this approach.
The
test inoculum is recommendedly prepared from a subcultured plate or, again,
from that pellet of the broth. It can be
prepared from a broth culture. The
recommendation by the manufacturer is the turbidity has to be a McFarland 1
standard which is very heavy inoculum for practical purposes, much heavier than
what you would see when a blood culture is initially detected as positive.
The
test time to perform this cell-lysis hybridization and detection is less than
one hour. So this would truly be
considered a rapid test. Marlow, last
year, reported that the limit of detection with seeded blood cultures was
approximately 10,000 colony-forming units per milliliter with this method. That is at least 10-fold to 100-fold more
sensitive than the limit of detection for the blood culture instruments.
In
other words, with a seeded study, it appears that you could use the blood
culture broths directly to do this test.
I think additional tests have to be performed to confirm this but if
this, in fact, is true, this would be an attractive alternative for identifying
Staph aureus rapidly from a blood-culture broth.
Still,
the way that you can get around the possible problems of sensitivity here would
be to pellet the organisms in a concentrate and use that to perform the
test. That should work very
successfully.
(Slide.)
The
last technique for identification of staphylococcus that I wanted to mention is
fluorescent in situ hybridization or FISH test.
Applied Biosystems, which used to be called Boston Probes, developed a
FISH test using synthetic peptide nucleic-acid probes that target, again, the
messenger RNA of the specific bacteria, in this case, Staph aureus.
They
have a number of probes for different bacteria but the one that we are
interested in today is the one for Staph aureus. The peptide nucleic-acid probe
is a synthetic pseudopeptide that hybridizes complementary nucleic-acid
targets. Essentially, it is a synthetic
peptide backbone with nucleic acids attached to it that would match up and be
complementary to the nucleic-acid target.
The
probes have the advantage of a higher specificity and more rapid hybridization
kinetics compared with traditional DNA or RNA probes. In addition, the hybridization can be
performed in a wide variation of salt concentrations which allows the speed in
which this reaction can be performed.
The
probes also have a fluorescent label on them which allows detection by
fluorescent microscopy.
(Slide.)
I
apologize for this picture. This wasn't
really what I wanted to show you. What I
wanted to show you is what is here in this lower right-hand corner but I am not
sophisticated enough with computer to figure out how to cut that little picture
out and show that alone.
So
this is from one of Boston Probe's research articles that were published. It showed a series of different
organisms. There was an E. coli. Salmonella is No. 2. No. 3 was Pseudomonas auruginosa and No. 4
was Staph aureus.
The
first two columns going down showed auto-fluorescence. The next four columns, they used specific
probes. So, under C, it was the specific
probe that was for the E. coli and only the E. coli is fluorescing. The second one was for Salmonella. The third one was for Pseudomonas and the
last one, in the lower corner here, was the specific probe for Staph aureus.
Truly,
that is what it looks like when you perform these tests. They really do jump out at you. The organisms can auto-fluoresce and they
have corrected with special filters for the auto-fluorescence. So it really is a fairly nice, in my
experience, and we have used this now for about three months; it is a system
that works fairly nicely.
The
downside of this is the total test time is approximately two-and-a-half
hours. It is not a problem if your blood
cultures are detected early in the day but if it is detected late in the day
and, because of the, I think, relative sophistication of the interpretation of
the reaction, it is not a test that can be performed off-hours. There
have been three studies using these probes; specifically, the Staph aureus
probe with positive blood-culture broths and the sensitivity and specificity
for each of the studies was 100 percent.
So it appears that this is a very sensitive and specific reaction when
used with blood-culture broths.
I
think that was my last slide.
DR.
LEGGETT: Thank you, Dr. Murray.
Questions from Committee
DR.
LEGGETT: Are there any questions? Don?
DR.
PORETZ: Through the years, it is obvious
that we are seeing more and more blood cultures being reported back as
coagulase-negative Staph. Not all those
patients have lines in place. Do you
think it is because of the way the blood is collected? Do you think it is because what is happening
in the laboratory? Why are we seeing so
much coagulase-negative Staph in blood cultures?
DR.
MURRAY: I could probably make one
comment about the laboratories. In my
opinion, one of the advantages for the new blood-culture systems is they are
noninvasive systems. Once you have
inoculated the blood into those, you don't go back into those bottles where
traditionally, either with manual systems or with the early automated systems,
there are multiple entries into the bottles. So
it is most likely the collection problems.
DR.
PORETZ: I get the impression, after
watching our laboratory technicians draw blood, at least in my hospital, they
are not as careful as they were several--they are being--you know, it is a
matter of dollars and cents. They speed
these people up from person to person. I
think that is probably the major reason and we are getting what we are paying
for. We are, therefore, treating more
patients than we need to treat, unfortunately.
DR.
MURRAY: Very clearly, and there have
been, I think, excellent studies that have looked at this, if you have a
dedicated phlebotomy team that collects blood cultures, you get much better
results. If you have technicians that
have other responsibilities, if you have nurses that have other
responsibilities, you have medical house staff that are doing a lot of
different things, they are not trained well and they don't take the time to do
it properly.
Again,
my experience is if you look at where you have problems, you can usually
identify key areas. That is really where
the laboratories need to focus their attention in getting the proper cultures
collected.
DR.
LEGGETT: John?
DR.
BRADLEY: It is wonderful to see the
progress in molecular techniques in increasing how quickly we can identify
organisms once they have come out of culture.
However, at the bedside, for enrollment in a study, what we would really
like is a test, a molecular test, we can do on plasma of the sick patient so
that, within two-and-a-half hours of entering the hospital, we would have
something to let us know whether they are infected or not. Can you comment on progress in that direction?
DR.
MURRAY: I think that the difficulty
that, if you look from the microbiology perspective, the difficulty that you
are working with is there are very small numbers of organisms present in the
blood and that you have to amplify that.
Not every company that makes molecular probes has targeted blood
cultures as the place to go because, if you come up with a successful system,
it is wonderful because there are a lot of people that would want to run those
tests.
I
am not optimistic about that, but possibly that will happen. Other approaches would be to look at a
patient's response to the organisms, and so you look at cytokine profiles. There is a lot of work that is being done
with that as well. And that is part of
problem. It is not specific.
DR.
LEGGETT: Barth?
DR.
RELLER: I would like to add three more
reasons, Don, why there are more positives.
One is where the blood is collected from. There are more and more catheter draws
because it is convenient. Two is time is
money, and the speed. If one uses
povidone iodine, as Pat pointed out, it takes time so that you have--and the
Gram-positives are the hardest ones to kill or to disinfect.
The
third thing that is, I think, unequivocal and has been shown in controlled
clinical trials is the newer instruments including media for institutions that
use charcoal and resin-containing bottles.
They are more sensitive. But they
are also more sensitive at picking up that solitary coagulase-negative
staphylococcus that is derived from the first two issues.
So
there is a tradeoff. You get more reals
but you unequivocally get more contaminants.
I would reinforce Pat's assessment of John's query about PCR. PCR, or nucleic amplification, is fantastic
for some entities where the number of targets is large; acute HIV infection,
hepatitis C, HSV, et cetera. Pat
emphasized it is unequivocally true, many, and shown by Washington, Murray,
others, at least half, more than half, of real staphylococcal bacteremias were
less than one organism per ml, so that one would have a large volume.
There
are currently not yet processes in place, not that it couldn't be developed,
that one could extract the 20 to 30 mls of blood, because if you don't have a
target, you don't have a positive nucleic acid.
DR.
LEGGETT: Dr. Murray, a question. On your slide about interpretation of culture
results, it stated that Staph aureus is detected in less than 24 hours and
other Staph greater than 24 hours. Are
you implying less inoculum or slower growth?
DR.
MURRAY: It probably is not the inoculum
effect. It is probably more related to
the rate of growth of the organisms. If
you just look at colonies of Staph aureus and colonies of coagulase-negative
Staph on a plate, generally the Staph aureus is a much larger organism, the
colonies. So it is growing faster.
The
inoculum is an important issue though because the time to detection is
influenced by the number of bacteria that are present. One way of assessing whether a catheter is
the source of a positive culture, or a septic patient, is to look at how fast
the organisms--how fast the cultures collected from a catheter group compared
with cultures collected at the same time from a peripheral vein.
DR.
LEGGETT: Any further questions? Thank you, Dr. Murray.
Do
we want to take a fifteen-minute break now?
I think so. I was chided by one
of the speakers last time because I wasn't accounting for older bladders. So it is now 10:15. Let's come back at 10:30 for the Open Public
Hearing.
(Break.)
Open Public Hearing--Extra
Session
DR.
LEGGETT: This will begin our extra session
of an Open Public Hearing which was not on the Federal Register Announcement.
Before
we have Dr. Tally speak to us, I would like to make the following
announcement. Both the Food and Drug
Administration and the public believe in a transparent process for information
gathering and decision making. To insure
such transparency at the Open Public Hearing session of the Advisory Committee
meeting, FDA believes that it is important to understand the context of an individual's
presentation. For this reason, FDA
encourages you, the Open Public Hearing speaker, at the beginning of your
written or oral statement to advise the committee of any financial relationship
that you may have with any company or any group that is likely to be impacted
by the topic of this meeting.
For
example, the financial information may include a company's or group's payment
of your travel, lodging or other expenses in connection with your attendance at
the meeting. Likewise, FDA encourages
you at the beginning of your statement to advise the committee if you do not
have any such financial relationships.
If
you choose not to address this issue of financial relationships at the
beginning of your statement, it will not preclude you from speaking.
Dr.
Tally?
DR.
TALLY: In the spirit of what Jim just
said, I am the Chief Scientific Officer of Cubist and I am a stockholder of
Cubist.
(Slide.)
I
would like to thank the agency for inviting Cubist to present at this important
advisory committee meeting. We are
currently in trial in a study of Staphylococcus aureus bacteremia
endocarditis. I would like to present
some of the experience we have had with this particular study.
I
will give you the summary up front using the old teacher attitude of I am going
to tell you what I am going to tell you, tell you, and then review it at the
end.
(Slide.)
Staphylococcus
aureus bacteremia, as we have heard from the previous speakers, is a
significant unmet medical need. It is a
heterogenous population which includes endocarditis and in these heterogeneous
populations, there are different outcomes.
There is a lack of a placebo effect with Staphylococcus aureus
bacteremia and I will address that during this talk.
It
is a difficult study to do, a bacteremia endocarditis study, but it is possible
and we will look at that today. However,
when we look at this, traditional noninferiority assessment may not be best or
the only association of efficacy in this seriously ill group of patients.
(Slide.)
What
is the high unmet medical need? We have
heard, from the earlier speakers, that Staph aureus is a leading cause of
bacteremia. It is a virulent
organism. Indeed, it is one of the
premier pathogens to infect man. It was
discouraged in the preantibiotic era. It
leads to endocarditis, metastatic infections and/or death.
As
we have heard this morning, Staphylococcus aureus bacteremia is both a cause
and a result of endocarditis. Finally,
there is changing epidemiology, as we have heard today and, in that changing
epidemiology, it is a therapeutic challenge and that is compounded by the
increasing resistance to beta-lactam drugs and the increasing tolerance to
vancomycin.
(Slide.)
What
is the mortality and what is the frequency of Staph aureus bacteremia? This is data just published in August from the
SCOPE study looking at 20,000 isolates of nosocomial bacteremia published in
CID. When you look at coag-negative
Staph, it is 31 percent of the isolates, the coag-negative Staph, with a crude
mortality of 21 percent.
With
Staph aureus, incidence of the 1999 survey, SCOPE survey, was 16 percent in
2004. It has jumped to 20 percent
of the isolates. So Staph aureus as a
cause of nosocomial bacteremia is increasing.
The intended mortality, the crude mortality, with Staph aureus, in this
particular study was 25 percent.
(Slide.)
What
about the placebo effect. This is data
that was mentioned earlier. The Skinner
study published in the Archives of Internal Medicine in 1941 looked at the
outcome in patients with Staph aureus bacteremia and the case-fatality ratio
was 82 percent. You will notice if you
are 50 or older, which most of us are in the room, the mortality goes up to
almost 100 percent.
With
this, when you look at Staph aureus endocarditis non-treated, it is 100 percent
fatal as are other endocarditises in the preantibiotic era. So the placebo effect in Staph aureus
bacteremia or endocarditis is little or none.
(Slide.)
The
next confounder in Staph aureus bacteremia is whether the patient has a MSSA
bacteremia or an MRSA bacteremia. This
is a slide from Sarah Cosgrove's meta-analysis looking at that. If you look at mortality with MSSA, it is
23.4 percent. With MRSA it is 36.4
percent. She controlled for confounding
variables in clinical backgrounds. So
there is a consistent finding that mortality is increased when you have MRSA
causing the infection.
(Slide.)
When
you do have MRSA, the main therapeutic modality has been vancomycin. The problem emerging from vancomycin has been
the emerging resistance. We saw VRE
outbreaks in Europe in '86. It continues
to today. VISA was first reported from
Japan in 1996. We still see it albeit it
is very low. Heteroresistance in vanco
was noticed by the CDC in 2001 and it continues to be a rising problem.
More
recently, we have had vancomycin-resistant Staphylococcus aureus albeit there
are only three isolates known at this time.
(Slide.)
When
you do look at vancomycin in this particular area of therapy for MSSA and MRSA,
two things come out. One, Chang, in an
analysis of over 500 cases of bacteremia, looked at MSSA, whether it was
treated with vancomycin or nafcillin. In
that study the conclusion was that nafcillin was superior to vanco in the
treatment of MSSA bacteremia and why most people recommend switching off vanco
to nafcillin when you have nafcillin-susceptible.
More
recently, there has been disturbing data with these heteroresistent strains and
vancomycin has been known to fail in MRSA bacteremia back into the early 90s in
studies coming from San Francisco.
The
heteroresistance and tolerance problem probably is the most common problem we
are seeing now and it has increased and heteroresistance is noted to be
associated with increased failures.
The
most recent paper in JCM in June of this year looked at a biased sample of
failure patients, looking specifically at the MIC of the organisms to vanco,
came up with a surprising result. By
NCCL criteria, an isolate with an MIC or 4 or less to vancomycin is considered
susceptible. However, when the group at
the Deaconess looked at 30 isolates, it had some rather disturbing outcome when
you broke up the isolates based upon the MIC.
Those
isolates with an MIC of 0.5 or less, there was a successful outcome in this
group of 55 percent. The overall group
of 30 patients, it was a 23 percent favorable outcome. However, if the isolate had an MIC of 1 to 2,
the favorable outcome was 9.5 percent and that is approaching what we saw with
the placebo effect that Keefer published in 1941.
So
one has to look at vancomycin in this group of patients and particularly wonder
about these ones with MICs of 1 to 2.
(Slide.)
So,
with that background, when we were looking at our drug, daptomycin, and how to
guide physicians in treating, and, particularly, what we were asked is how do
we treat bacteremia, we made the decision back in 1999 to look at patients with
bacteremia and endocarditis because, at that time, endocarditis is a
registerable indication according to FDA guidelines.
In
consultation with the FDA, we undertook at study of daptomycin and infective endocarditis
and bacteremia to specifically Staph aureus.
The criteria to get into the study is you had to have a positive blood
culture for Staph aureus. It is
multicenter, both in the U.S. and Western Europe. It was randomized. But, because of safety concerns, it was an
open-label study which adds complexity that I will talk about in a minute.
We
did add a blinded external adjudication committee. It is a comparative control and it was
nafcillin versus vancomycin. In the
beginning, we just treated bacteremia and right-sided endocarditis. There was an amendment of the protocol in
April of 2004 to include a left-sided endocarditis.
(Slide.)
What
were the challenges in this study? You
have heard this morning that Staphylococcus aureus bacteremia is a
heterogeneous group of patients. We use
the modified Duke criteria to try and give some semblance of what type of
patient we had at admission criteria.
This is the phenomenon. The
clinician is confronted with a positive Staph aureus blood culture and you
don't know which group they are going to fall into. You only determine that during the course of
therapy with many diagnostic tests.
What
we did is we classified our patients by the Duke criteria into definite or
possible or not infective endocarditis.
Part of that was a centralized reading of our echos, not leaving it to
the original site. Finally, at the end,
there will be an overall determination of responses in each subgroup; that is
left-sided endocarditis, right-sided endocarditis and bacteremia.
This
is a difficult study to enroll and I will show you the magnitude in the next
couple of slides.
(Slide.)
So
what we did is enrolled numerous sites.
There were some ethical considerations and that was you are treating
patients with a high mortality if they have endocarditis. So the treating physician has to know. We looked at that open-label design. We also put in place a safety data-monitoring
committee to make sure there was not a safety issue in the ongoing study.
What
about the bias due to an open-label design?
We addressed that somewhat with the blinded independent external
adjudication committee. It is composed
of ID experts that are experts in infective endocarditis. They will determine diagnosis and outcome.
Finally,
with the type of study here, we have heard about relapse, you need long-term
follow ups. So the test of cure is
actually out at six weeks and a post-study visit is actually out three
months. So the length of the study is
rather long.
There
are extensive inclusion and exclusion criteria which affect the conduct of the
study and it is related to the drugs used and the patients being enrolled.
(Slide.)
How
did we make out in this study? When we
looked at our diagnosis, and we are over 200 patients which is what are target
was, and we looked at, by the Duke criteria, at these patients, about a third
of them did not have IE based upon the Duke criteria and would consider those
having bacteremia.
We
had a large group that were possible IE.
They met the Duke criteria but they did not have a positive echo. Finally, we also had a smaller group that had
definite infective endocarditis. It is
proven by echocardiography.
(Slide.)
How
many patients did we have to screen to get this over 200 patients? We screened over 5,000 patients to get this
over a two-and-a-half-year period. But
it is doable. And we are, at this
point--right now, we are in discussions with the FDA on going forward with this
particular study.
(Slide.)
So
I am back to the summary from the beginning.
There is a significant unmet medical need. I think it has been brought out time and
again this morning. The heterogeneous
population includes patients with endocarditis and these heterogeneous
populations all have different outcomes.
So you are going to have to do some type of subanalysis of those groups.
There
is a lack of a placebo effect in this so it raises some questions we will get
to. It is a difficult study to do,
expensive, but it is possible to do these studies as we have shown.
Finally,
traditional noninferiority assessment may not be best in this serious illness
or the only assessment of efficacy and I would throw that open for discussion
at the end.
Thank
you.
DR.
LEGGETT: Thank you, Frank. We will take some questions. Alan?
DR.
CROSS: When you said that you screened
over 5,000 patients, was that 5,000 patients with positive blood cultures or
with Gram-positive positive blood cultures?
DR.
TALLY: It was 5,000 patients with
positive blood cultures.
DR.
LEGGETT: Jan?
DR.
PATTERSON: I was wondering on that
Sakoulas JCM 2004 study, the vancomycin--we know that physicians tend to
underdose vancomycin. I was wondering,
did they use a 10 milligram per kilogram dose and/or were there any trough
levels measured?
DR.
TALLY: There were trough levels and they
were, I think, above 15. So they took
that into consideration with these.
DR.
LEGGETT: Frank, could you elaborate a
little bit about the exclusion--was it mostly the inclusion-exclusion criteria
that you had the 5,000 but only 200 enrolled?
DR.
TALLY: I have my Dave Letterman list of
ten reasons. The biggest reason, in our
study, turns out to be creatinine clearances below 30. Our drug is cleared by the kidney. We didn't have guidance in that area so it
was a major exclusion criteria in this.
And, indeed, that is something we are working on now to try and include
patients in the future with ongoing studies of patients with renal failure
being evaluated with a specific dosing regime.
It
was not the only reason. That was a
primary reason and, in those patients, they probably had other reasons for
being excluded also. But, also, there
were a whole bunch of other reasons.
One, they were already on the drug for greater than 48 hours, it was
effective. Two, you couldn't get the consent
in this serious illness. Three, there
was renal failure. Four, they were in
imminent threat of death so we didn't want to put morbid patients in. Fourth--let me pull out my sheet, my
cheat-sheet for that.
A
large group where they intravascular material that couldn't be removed were
excluded. Severe neutropenia. Elevated bilirubins above 3. So there were a number of these criteria to
try and focus on the disease and get it.
We are not giving out the exact numbers on that. We have submitted all of that data to the
FDA. We will be discussing that and it
will come out sometime when we complete the study.
DR.
LEGGETT: Tom?
DR.
FLEMING: Could you clarify your last
point? It is somewhat vague. You haven't gone into any details about what
type of noninferiority assessment was planned.
DR.
TALLY: Excuse me?
DR.
FLEMING: Could you clarify your last
point about the noninferiority assessment.
DR.
TALLY: Not being a statistician, I
can't. I don't know what type of
analysis should be done and that would be something we should talk about. But I think with the number of patients that
you have to enroll, you would have to screen, to enroll just 200 patients. And then you have to do a subset. If you want to look at the subset analysis of
the different groups of patients within here.
It is going to make it an impossible study to do if we are doing a
noninferiority study.
So
one would like to know if there are alternate ways to study this group of
patients that, one, do not have a placebo effect; two, have a definite endpoint
of you either clear the bacteremia or you don't. Third, to take into those the effect of not
being able to do a study to assess all of these subgroups.
So
I, personally, don't know what type of analysis should be done and would throw
that out.
DR.
FLEMING: Just to lay out the principles
here, though, the analysis that you would do should allow you to conclude that
you have an efficacious intervention.
DR.
TALLY: Correct.
DR.
FLEMING: And in a setting that you are
referring to here as--you are calling it lack of a placebo effect. I think what you are saying is a setting
where you are going to have very few favorable outcomes in the absence of
effective therapy.
DR.
TALLY: Correct.
DR.
FLEMING: But where there are effective
therapies then a critical question is to ensure that an intervention isn't
clinically meaningfully worse than what, in fact, you could achieve with
existing therapies which also is, in fact, addressable through a noninferiority
paradigm.
DR.
TALLY: I think you hit on it. It is the clinical evaluation of it and that
is what we are in discussion with the FDA right now.
DR.
FLEMING: Celia?
DR.
MAXWELL: On your Slide 12, on the
diagnosis of enrolled patients by the modified Duke criteria at baseline, I had
a question--two questions, actually, of the definitive and the possible
infective endocarditis, what was that in actual numbers and also, of these two
populations, were any or what percentage of them in each of these categories
were shown to have vegetations, let's say, on echo.
DR.
TALLY: The definites had echo evidence
of vegetation.
DR.
MAXWELL: All of them. And what number was that?
DR.
TALLY: Oh; we are not giving out the
numbers at this point in time.
DR.
MAXWELL: Okay.
DR.
TALLY: Because the numbers are not
complete. We are on an ongoing study
where there are a number of patients where we haven't determined--they are
under analysis. So I am constrained from
giving out numbers because, in addition to being regulated by the FDA, I am
also regulated by the SEC. And I don't
want to give out any misleading information.
DR.
LEGGETT: Don?
DR.
PORETZ: Frank, do you anticipate, if
this drug is of value and is approved, is one going to be, when they are
treating infective endocarditis, obligated to get serum levels of the drug?
DR.
TALLY: Since I haven't seen the data and
the study is still ongoing, I think we have to wait to draw that
conclusion. We had built into the study
a pharmacokinetic study on all patients that we will be able to use when we
look at the outcomes when the study is closed down and the blind is broken.
DR.
LEGGETT: Barth?
DR.
RELLER: I just wanted to comment that,
at first, it seems the 200 out of 5,000 is a small number. But it is exactly what one would expect given
the physiologic exclusions. I base that
on the largest review published in the '90's on bacteremia; exactly 9 percent
of all positive blood cultures grew Staph aureus assessed by an
infectious-disease clinician to be true, which were almost all of the Staph
aureus.
What
it is telling you is that half of all blood cultures obtained in tertiary-care
hospitals in the United States are contaminants or unknown. So you do the numbers and, if you took 1,000
reals relative the positive, same institution, it is 9 percent. So basically it is capturing half of the ones
who really have it.
DR.
LEGGETT: Yes.
DR.
FETZER: (Inaudible comments.)
DR.
LEGGETT: Could I ask you to speak into
the microphone, please, and identify yourself.
DR.
FETZER: Olaf Fetzer, senior vice
president, Cubist Pharmaceuticals, responsible for R&D. I just wanted to mention to Frank, as a
correction; of the 5,000 screened, these were all Staph aureus confirmed.
DR.
RELLER: It wouldn't make it much
different if it were all staphylococci in coming down to--but then there are
other reasons why people chose not to enter someone into the trial apart from
the exclusion criteria mentioned.
DR.
TALLY: In response to Bob's question,
one, and to clarify, the only patients that were screened has positive Staph
aureus cultures. So that has been
eliminated right away. There are a whole
list--there are about 30 reasons why patients didn't get into the study. I gave you some of the top ones and I don't
have the full list right with me.
If
somebody drops out for one of the higher reasons, it doesn't mean they have a
lower reason for exclusion. What it is
saying is that this--and it is a very sick patient population--when you build
in your exclusion and inclusion criteria, it eliminates a lot of patients. It is just getting that proper window where
they haven't had other therapies and getting a patient to consent to your study
and to get the physician to take out devices is problematic in this group of
patients.
DR.
RELLER: I was just running the numbers
based on the earlier question and on the comment that it was all positive
cultures, not all cultures obtained. If
one did all positive cultures, you could count on, at most, 9 percent.
DR.
LEGGETT: Thank you. Let's move on. Thank you, Frank.
Our
next speaker is Dr. Powers who is going to talk to us about clinical-trials
issues with studies of Staphylococcus aureus bacteremia which will be followed,
again, by questions from the committee.
Clinical Trials Issues with
Studies
of Staph aureus Bacteremia
DR.
POWERS: Thanks, Dr. Leggett.
(Slide.)
I
think that is a good introduction because what Dr. Tally brought up--
DR.
LEGGETT: Excuse me, John. I have to close the Open Session.
DR.
POWERS: Oh; go ahead.
DR.
LEGGETT: The open session is closed.
DR.
POWERS: That took care of that. What Dr. Tally brought up was that it was
very hard to evaluate the endocarditis subset within the group of people with
Staph aureus bacteremia. But what they
did find was 5,000 people with Staph aureus bacteremia.
So
what I would like to talk about today is can we define a new indication of
primary bacteremia due to Staphylococcus aureus and then maybe look at subsets
within that to try to evaluate those patients.
(Slide.)
So
the first thing we are going to talk about is actually defining this indication
and ask the committee whether they think that this is a worthwhile indication
for people to pursue and does it actually add some information for clinicians.
Then
we would talk about the place of this potential indication in a
clinical-development program and what kinds of preclinical and prior
clinical-trials work would be helpful in evaluating a drug that would be
potentially helpful in this disease and then, finally, go through some of the
issues in designing and analyzing clinical trials of this potential indication.
We
will go through some of those issues of selecting the appropriate patient
population to study, talk about how would we evaluate endpoints with what Dr.
Nambiar brought up about how would one evaluate metastatic disease that may
occur on treatment, talk about this issue of selection of duration of therapy,
the issue with controlled drugs--and we will go into a little bit about this
dictum of vancomycin and nafcillin and how they compare to each other, and then
some of the statistical considerations including the question Dr. Fleming asked
about noninferiority.
(Slide.)
So
the first question we would like the committee to ask here, and I am going to
do this talk in terms of questions and then put some of the pertinent
information underneath it. So, should
primary bacteremia due to Staph aureus constitute a separate indication?
Before
we answer that, we actually have to say what is an indication. Well, an indication and the patients actually
studied should be something that we can clearly define. That is for two reasons. One, obviously, we need to be giving some
information to clinicians about how they appropriately select patients for
treatment with that drug once it is determined to be safe and effective. Also, we need to be able to write that into
prescription product labeling so that people can understand who was studied and
where the drugs should be used.
So
what we are suggesting is that maybe one definition of primary bacteremia due
to Staph aureus, and this gets back to what Dr. Patterson asked, we are not
defining in the same way as it was defined in some previous trials. What we saw was that it is variously defined
depending upon how you look at it.
So
our suggestion here would be that it is evidence of systemic signs and symptoms
with positive blood cultures for Staph aureus and no other identified source of
infection at the time of enrollment. The
reason why we brought up signs and symptoms is something that Dr. Reller just
brought up, that maybe as much as 50 percent of positive blood cultures don't
represent real disease.
What
the committee had discussed in the past, in 1998 and 1999, was that bacteremia
alone is not an illness. We need to link
that to some signs and symptoms that the patient actually has.
It
shouldn't be that hard because, usually, clinicians draw a blood culture when
the person is having some systemic signs and symptoms. So then the question comes up is should one
differentiate from secondary bacteremias--that is, patients who have a known
source of infection such as pneumonia, complicated skin infections, et cetera.
What
the committee had told us back in 1999 was they were concerned that there may
be differential efficacy of drugs based on the site of infection. We have certainly seen recent drugs that were
effective in, say, complicated skin but did not look effective in other body
sites like pneumonia. So, depending upon
where the patient's original site of infection is may be important in
determining drug efficacy.
Also,
bacteremia related to an intravascular catheter--when we looked through a lot
of this literature--is often really a diagnosis of exclusion. Sometimes it is based on a positive catheter
tip but, again, when we went back to the 1970s and tried to evaluate where does
that information come from on positive catheter tips, again, there really is no
gold standard to say what were those things compared to to determine that a
positive catheter tip actually implied that the person had a true
catheter-related infection.
So
the question came up, since it is often a diagnosis of exclusion and what we
have heard from people in industry that we will go over this afternoon is that
it is very often difficult to get that piece of information from the catheter
because it has often been discarded by the time you get around to the patient.
So
could we devise an indication where intravascular-catheter-related infections
were subsumed under this primary bacteremia indication. But, really, the question is would this
indication provide useful information to clinicians. If we already know that a drug is effective
in Staphylococcus aureus infections with a primary source of infection, would
this provide this some additional data to knowing that the drug is effective in
pneumonia, complicated skin, et cetera.
That
brings up something Dr. Tally just talked about. Would this indication provide us the
opportunity to study patients that would not be included in those with a
primary source of infection. Namely
patients with endocarditis would be the big issue there.
(Slide.)
In
fact, it is such an important issue that does efficacy in primary bacteremia
due to Staph aureus imply that the drug is effective in endocarditis. Clinically, what we always worry about when
you see a person with a Staph aureus in their bloodstream, especially if they
don't have an identified initial focus of infection, is they may have an occult
case of endocarditis.
So
why is that important in terms of a clinical trial as well as clinically? Because, first of all, it implies different
outcomes in the patient and, in fact, Dr. Tally referred to a paper by Chang in
Medicine. There is another paper by the
same authors in that same journal that looked at risk factors for outcome in
people with Staph aureus bacteremia, 31 percent mortality in the people who had
endocarditis versus 20 percent in the people who didn't. So big difference in outcome if you have
endocarditis or not.
It
also may imply a different duration of therapy as well, and that remains
controversial; two weeks, four weeks, six weeks, what would be the appropriate
duration in these people.
So
then the question comes up is can these drugs be studied without examining
efficacy in endocarditis and, even within endocarditis, are there differences
between right- and left-sided disease.
So one of the things we would like to ask the committee is can these
drugs be studied in a staged approach of first studying uncomplicated Staph
aureus bacteremia or at least people unlikely to have a complication; then
study right-sided endocarditis; then study left-sided disease.
In
addition, how would we approach drugs that may not demonstrate some potential
efficacy for endocarditis based on either in vitro or animal testing but still
may be effective in patients who have a primary source without endocarditis.
(Slide.)
So
the next question that comes up is where would these kinds of studies fit in
the overall clinical-development plan for a new drug. We brought these issues up in April of 2004
at a public workshop co-sponsored by FDA, the Infectious Disease Society of
America and the International Society for Antimicrobial Pharmacologists.
Some
of the participants, when we brought this up, a little to our surprise, were
very hesitant about going forward with studying drugs without some prior
information that the drug may be effective given the serious nature of this
disease and the potential for development of endocarditis.
(Slide.)
One
of the things that the folks at that meeting suggested was that there should be
some data from trials in this indication and that this kind of indication
probably would not be the sole basis for approval. In other words, if a new drug came forward
and this is the only thing they wanted to study, that that might be problematic
and that we would probably look at this in terms of the overall efficacy of a
drug in treating serious Staph aureus infections.
So,
again, they expressed this view of that we needed some more infection. So then the obvious question is what kinds of
information would be helpful prior to studying a drug in a serious disease like
this.
(Slide.)
The
first question is what kinds of preclinical studies would be helpful in forming
these hypotheses about potential efficacy and safety in this indication. And that would include both in vitro data and
animal models. The in vitro data would
consist of looking at the biological activity against isolates of Staph aureus
and that brings up another interesting question about what is the clinical
significance of bacteriostatic versus bactericidal drug.
Dr.
Pankey and colleagues wrote a very interesting review of this just recently in
March 2004 in Clinical Infectious Diseases where they actually proposed the
hypothesis that no drug is really all bactericidal or all bacteriostatic, that
the way in which we define these things is really 80 percent or so killing with
a bacteriostatic and 99 percent of so with bactericidal and that, by altering
the conditions of inoculum, pH, et cetera, that you can actually alter whether
a drug is bacteriostatic or bactericidal in the test tube.
The
real question, though, is what is the clinical significance of bactericidal
versus bacteriostatic. We have all been
taught that, in serious diseases where the antibiotic may not penetrate or
there is little help from the host immune system such as meningitis and
endocarditis, that at least, in animal models, it appears that bactericidal
drugs look more effective in those models.
So
the question is what do you do, then, with a drug that appears bacteriostatic
in the test tube. Would that be
something that folks would be able to study in this indication or could we use
that staged approach that we talked about earlier.
Again,
could we look at, then, some animal models of infection to give us a better
idea of how these drugs may work given that in vitro may not reflect clinical
outcomes perfectly and what kind of animal models would we need. Endocarditis would seem to be an obvious one
but are there other potential metastatic sites of infection like bone that we
would want to look at animal models as well.
(Slide.)
Then
what clinical experience would be helpful in evaluating a new drug for this
indication? We know that spontaneous
generation in the bloodstream was done away with a number of years ago as a
potential reason why people have organisms so, obviously, these people have a
primary site. It is just that we don't
find it. So patients with no primary
site, it is still coming from somewhere although it may be occult.
The
serious nature of this illness and, again, those potential differences in
efficacy of drugs based on the primary site of infection, again, would weigh
against this being the sole basis of approval for a new drug.
So
one of the things we would like the committee to address is what kinds of data
from clinical trials of infections of sufficient severity where Staph aureus
would be a potential pathogen would be helpful in evaluating in new drugs for
this indication.
Some
of the ones we thought of were hospital-acquired pneumonia, community-acquired
pneumonia sometimes especially after influenza outbreaks can occur due to Staph
aureus, complicated skin and skin-structure infections and are there some
others that the committee might suggest where Staph aureus is a common pathogen
that we may be able to look at.
So
I would like to go into now a bit of--now that we have gone into the natural
history of the disease, how will we actually design and analyze clinical trials
for this indication. One of the reasons
we did the talks the way we did today was it is very important to look at the
natural history of a disease and to design trials based upon that natural
history.
These
clinical trials obviously need to provide information that is useful in clinical
practice but it is a very important distinction to realize that clinical trials
are not clinical practice. We do lots of
procedures to people in a clinical trial that are not routinely done in
clinical practice but, perhaps, the biggest difference is that, in clinical
practice, we give a drug and we don't care why the patient gets better as long
as they recover.
However,
in a clinical trial, what we are trying to do is to ascribe causality of
results to the drug that was administered, a very different thing than what we
do in clinical practice. So, to allow us
to do that, we use the scientific method and that is we hold as many factors
constant as possible other than the drugs administered to the patients so that
we can ascribe the causality of those results to those drugs that were
administered.
The
Code of Federal Regulations actually says this in a very nice way. It says; the purpose of performing any
clinical investigation is to distinguish the effects of the drug from other
influences such as spontaneous change in the course of the disease, placebo
effect or biased observations. There are
a number of other things such as potential confounders that may come into the
trial like concomitant medications, et cetera, that also impact on that as well.
(Slide.)
So
I wanted to sort of show this as a map and talk about the places where
potential bias may creep into a trial and then try to address some of these in
terms of primary bacteremia due to Staph aureus indication.
So
what we first do is we obviously take a group of people as a whole who have the
disease or even, more importantly, that we think might have the disease and
then try to define the patients who would enter into the trial. Clearly, the first step there is we want to
make sure they have the illness that we are trying to study.
The
issue here, too, is that this population needs
to be heterogeneous enough to extrapolate to the people we are going to
treat in practice but homogeneous enough to be able to make some conclusions
about drug efficacy. Then we randomize
people and, hopefully, blind this as well, talk about things that may occur
while patients are on therapy, appropriate endpoints and how we analyze the
data.
(Slide.)
So
the first issue there is defining the patients who would actually come into the
trial which is based upon the inclusion and exclusion criteria. Again, as I said, we need to strike a balance
between a homogeneous enough population to study so that outcomes are not related
to the differences in the natural history of the disease just like the Code of
Federal Regulations said we are not trying to measure and that they are related
to drug effects, but has to be heterogenous enough to be able to extrapolate
this to clinical practices.
One
of the first issues is we would need to differentiate among patients with
Gram-positive cocci in the blood. Dr.
Murray gave us a good talk this morning about how we may be able to do this.
One
of the issues we have seen is that if you go to the microbiology laboratory and
try to use that as the way to screen for patients in these trials, what is
going to happen is, a, you are going to get a lot of Staph epidermidis and,
even if they have Staph aureus, those people are likely to have received some
amount of therapy by the time you get back to the patient who is up on the
floor.
So
the question we like to ask the committee here is are there better ways of
screening for patients than just getting the breakdown of who comes out of the
microbiology lab. More and more, as we
see these trials, we are beginning to see that especially in shorter-term
illnesses that that one or two days of antibiotic that people get up front may
have a big influence on the outcome at the other end. So that may not be an insignificant problem.
Again,
these newer diagnostic tests that Dr. Murray talked about may allow us to
differentiate Staph epidermidis from Staph aureus prior to enrollment which
would be a huge benefit because, otherwise, the drop-out rate from these trials
may be considerable.
(Slide.)
Again,
we know that there are different natural histories for various populations of
patients in whom subsequent testing after randomization may show a source or a
metastatic site of infection, such as endocarditis. Again, I mentioned the difference success
rates and the different durations of therapy that may be necessary depending
upon what infection site the patient ultimately has although it may be
difficult prior to enrollment to differentiate those people.
As
Dr. Nambiar presented, even patients with what may be considered uncomplicated
disease such as catheter-related infections may subsequently develop metastatic
disease. So all of these things we are
looking at are risk factors for metastatic illness but does not obviate that
the patient may then develop those sites of infection on therapy.
(Slide.)
One
of the things that we always find very important at the FDA is what you call
something and the name of an indication.
So I wanted to be clear about some of the definitions that we are using
here today. One of them was complicated
versus uncomplicated disease. Again,
looking through the literature, we found various definitions of what you would
call this. In fact, in the study by
Small and Chambers that Dr. Tally referred to, what we found is that what they
called complicated was just somebody that continued to have fever which is a
very different issue than what we saw as complicated in some other trials.
So
what we put out as a trial definition for you folks to discuss is complicated
disease would be patients who develop further clinical manifestations that were
not present at the time of initial diagnosis that may portend a worse prognosis
and/or need for prolonged therapy.
As
Dr. Nambiar said, these can be divided into two categories; severe sepsis, ARDS
and DIC which usually occur within 48 hours but then that issue of metastatic
sites of infection which may occur early on, may occur later, and some
preliminary evidence that we found says may actually decrease with the
institution of effective therapy. But
you saw the limitations of the data that we were able to find.
What
we haven't really found to be very useful is this distinction between
community-acquired versus nosocomially-acquired infections. When we look through the literature, what we
saw is this really wasn't referring to the geography of where you got the
infection. It was really trying to refer
to different host populations.
Although
we have defined community-acquired versus nosocomial with diseases like
pneumonia, the question is does it really help us here. When we went back and analyzed our data from
the Focus Technologies database, we saw that these PVL-containing
community-acquired MRSAs which usually remain susceptible to clindamycin,
tetracycline and trimethoprim sulfa were really mixed in with the
multi-drug-resistant Staph aureus that you would normally think of as
nosocomial when we evaluated only outpatient isolates of Staph aureus.
So
what that tells us is sicker people are going home, getting mixed up out there
in the community with the people who have community-acquired MRSA and so, when
somebody gets sick in the outpatient setting, which one of those do they
have. It is not really the fact that
they got it as an outpatient that determines what is happening. It is really the host factors that determine
it.
So
our looking at this says this may not be as useful a distinction in clinical
trials for labeling given that there is such overlap in the populations. If we tell a clinician, use this for
community-acquired and that is a dialysis patient who is in and out of the
hospital every day, that becomes very confusing to the clinician.
(Slide.)
So
one of the issues here, obviously, is it is very difficult to stratify these
patients at the time of enrollment. We
brought up this morning this issue of could you wait a little while, see what
happens to these patients and then treat them later. Well, that data that shows that DIC, ARDS and
severe complications can occur within 48 hours would really argue against
waiting for any period of time.
But,
since we can't wait, these metastatic complications may occur after
enrollment. So, how well do these risk
factors that have been cited in the literature select patients who have
complicated disease and uncomplicated and, therefore, with uncomplicated, could
these people receive what has been called short-course therapy.
Nathan
Fieldman and I did our fellowship at Virginia.
One of our co-fellows, John Jernigan, did a study while we were there,
or a meta-analysis, looking back at all the studies that have been in the
literature up to that point in time on evaluating short-course therapy for
Staph aureus bacteremia.
What
John and Barry Farr found was that many of these studies differentiating
complicated from uncomplicated infection were retrospective and 10 of the 11
trials that they looked at that time were uncontrolled. It is very difficult to be able to make any
real good assumptions about whether short-course versus long-course has any
differences associated with it.
We,
then, went back and tried to pull all the studies from 1993 to the present to
see if there were any differences and all we found, again, was either
observational studies or retrospective studies.
So, again, even since 1993, there is not much new information that would
allow us to be able to draw any firm conclusions about short-course therapy in
this disease even if you had uncomplicated disease.
So
one of the questions we are going to ask the committee today is how do we deal
with that in terms of setting the duration of therapy.
(Slide.)
How
useful are these risk factors that have been enumerated in the literature in
the past in the clinical-trials setting.
Well, these may be useful in clinical practice but some of these risk
factors, like duration of fever and duration of bacteremia actually occur after
the patient has been randomized.
The
other thing is these are all based upon the fact the you have a known effective
drug. So, if a person is on nafcillin
and remains bacteremic for three or four days, you could say, well, I think
that person has endocarditis but I feel comfortable leaving them on
nafcillin. This is a different situation
where we are now testing an experimental drug in this setting, so does duration
of fever and of bacteremia say something about how well the drug is working.
So
how could we then use an outcome to define who the patients are at the
beginning of the trial. It seems like
very circular reasoning.
(Slide.)
The
other issue I wanted to bring up is, since these risk factors are based on
outcomes with known effective therapy--I brought that up already about
experimental drugs--how should patients who develop a site of infection after
randomization be handled. I think Dr. Fleming
asked this question earlier. Could
patients with no signs or symptoms at the primary site be left in the trial
when they develop a site of infection on therapy and does that have something
to do with the timing of when they develop that site of infection.
So,
if a person ends up in the trial and, within three or four days, develop
pneumonia, can we assume that that pneumonia was there? If they develop pulmonary emboli, does that
mean it was there at the time? Even if
it was there at the time, should we still call those people failures of therapy
in order to actually analyze people evenly between the arms of the trial.
In
the past, we have evaluated--in empiric febrile neutropenia trials, we have set
a breakpoint of calling people baseline versus breakthrough infections. But that presents another conundrum. If you set that breakpoint, suppose somebody
gets the infection one day before versus the person who gets an infection one
day after that breakpoint. Are those
people really different. That is a real
conundrum we are going to ask you to comment on today.
What
is really important here, though, is patients would need some kind of
standardized evaluation at the time of enrollment so that there are no
potential differences between arms of the study in determining who has baseline
infections and who does not.
So,
if one study center decides, we are only going to do chest X-rays and another
study center says, we are going to do chest X-rays, bone scans and CAT-scan
everybody from head to toe, the total body "groapgram," then how
would we match those two up. So there
would need to be some standardized way.
We realize you have to be practical about what you can do here and that
we can't ask for every test in every person.
But,
as Dr. Nambiar pointed out this morning, that one study actually showed that
you find what you look for. The harder
you look, the more likely you are to find the primary site of infection.
So
we are going to ask you today what tests would be appropriate and, given this
issue that endocarditis is such a concern, would every patient need some kind
of echocardiography to evaluate those patients for endocarditis given that even
patients with catheter-related bacteremias may go on to develop subsequent
endocarditis.
(Slide.)
So,
again, should patients who develop a site of infection be considered clinical
failures on therapy? Should one
differentiate baseline from breakthrough infections? And, again, can that be part of what we
consider as part of the endpoints in this disease.
When
we actually evaluated this, and I will go back to the paper that Dr. Tally
brought up by Small and Chambers that was published in Antimicrobial Agents and
Chemotherapy in 1990. What they did was
they took patients and, if their blood cultures were negative, and yet they
remained persistently febrile, they called those people failures.
If
they had some other complication, even in the face of a negative blood culture,
they were called failures. It is
interesting that we use that data to say vancomycin may not be so effective. But now, when we are talking about clinical
trials on the other end, how are we going to handle that and call those people.
So
it seems, when we were discussing this, that a negative blood culture doesn't
always tell you that the person is not going to go on to have some clinical
complication down the line. So would a
proper endpoint include not only negative cultures, which we clearly think are
important, but also some other evaluation of how the patient is actually doing
down the line.
The
other issue is this idea of time to negative blood cultures. This has been commented on several times in
the literature and probably goes back originally to the Kourzanowski paper in
the Annals of Internal Medicine in 1982 wherein patients with right-sided
endocarditis, they tested nafcillin plus gentamicin versus nafcillin alone.
I
put this in my category of urban legends of infectious diseases because we are
always told that we should use gentamicin up front for the first five
days. The first issue is that is now how
the study was done because the patients got gentamicin plus nafcillin all along
during the therapy and what they showed was that, in a subgroup analysis of
only non-addicts, eliminating all the addicts, which consists of 11 patients on
nafcillin and 19 on the combination, they showed 3.4 days of bacteremia in
nafcillin and 2.9 days in nafcillin plus gentamicin.
A,
is that a real difference anyway that is clinically significant, about a half a
day's worth of difference and then, after that trial was done, people say, well
there was more toxicity in the gentamicin arm, obviously renal
insufficiency. They said, well, since it
causes renal insufficiency, let's just give the gentamicin for five days up
front.
And
that is what we recommend. And that is
actually recommended in the American Heart Association guidelines. But that is not how it was studied. So that becomes an issue, too, for selecting
control regimens which we will get to down the line.
But
the real point here, in terms of this problem here, is that time to negative
cultures didn't correlate with either morbidity or morality in that
Kourzanowski study. So, even if you can
make the blood cultures turn negative faster, what does it mean clinically for
the patient down the line.
(Slide.)
The
next issue is how should the duration of therapies in studies of this
indication be determined. The first
question is why is that even important to discuss. Again, the problem here is we leave this up
to investigator discretion, we may introduce a potential bias that similar
groups of patients may be being treated with two weeks worth of treatment at
one center and four weeks worth of treatment in the other and how would we
compare those.
So
this is a big issue because we know that there is significant variation in
clinical practice even for uncomplicated disease. I know every time we brought this up when I
was a fellow and we would have a Monday conference about this, the attendings
would be throwing stones at each other back and forth about whether everybody
should get four weeks regardless just because they have Staph aureus in their
blood versus others who thought that you could select a population that should
get shorter-course therapy.
In
the terms of clinical trial, this would really need to be specified up front as
to what duration of therapy would be appropriate for what patients.
(Slide.)
So
the next question is how would appropriate control regimens be designed for
this indication. Let me go back, since I
didn't hear this until Dr. Tally presented his, I want to talk a little bit
about this vancomycin versus nafcillin distinction.
When
we went back and actually looked through this data, there are no randomized
controlled trials that actually compare those.
The first study or the most recent one is the one by Chang which was
published in Medicine in 2003. The
problem there is that we need to really understand the limitations of some of
this data.
While
that study evaluated 505 patients in a prospective manner, it was an
observational trial. An observational
trial is not randomized and the problem with that is that it may not, then,
account for some of the differences between the patient populations. Since it is also observation, they have no
influence on how the patients actually are treated which means that things like
management of the catheter is not controlled for in that population.
So
what they did, then, was come up with a relative risk for vancomycin. It doesn't mean that vancomycin is inferior
because there is no direct comparison between vancomycin and nafcillin within
that trial. So, again, there are some
limitations in looking at that.
The
study by Small and Chambers published in 1990 in Antimicrobial Agents and
Chemotherapy evaluated all of 13 patients who received vancomycin and they were
I.V.-drug abusers. Five of those 13
patients were considered failures. And,
again, we know that 100 percent of patients are not cured when they have
endocarditis. So what you really need is
some control, which that trial did not have.
What they then did was they went back and they pulled several papers which had essentially between 10 and 25 patients, pooled them all together and t